Trends in hepatitis C-related mortality in Switzerland.

In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the United States, HCV-related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995-31 December 2014) in HCV-specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV-related mortality to HIV-related and hepatitis B (HBV)-related mortality. To determine potential under-reporting in HCV-related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV-related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person-years. Since 2000, HCV-related mortality has been higher than HIV-related mortality and was about fivefold higher in 2014. HBV-related mortality remained low at ~0.5/100 000 person-years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV-related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV-related mortality remained constant, possibly because quality of care was high, or because of under-reporting or because mortality has not yet increased. However, HCV-related mortality is now much higher than HIV- and HBV-related mortality, and under-reporting was common.

On the potential of a short-term intensive intervention to interrupt HCV transmission in HIV-positive men who have sex with men: A mathematical modelling study.

Increasing access to direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection and decelerating the rise in high-risk behaviour over the next decade could curb the HCV epidemic among HIV-positive men who have sex with men (MSM). We investigated if similar outcomes would be achieved by short-term intensive interventions like the Swiss-HCVree-trial. We used a HCV transmission model emulating two 12-months intensive interventions combining risk counselling with (i) universal DAA treatment (pangenotypic intervention) and (ii) DAA treatment for HCV genotypes 1 and 4 (replicating the Swiss-HCVree-trial). To capture potential changes outside intensive interventions, we varied time from HCV infection to treatment in clinical routine and overall high-risk behaviour among HIV-positive MSM. Simulated prevalence dropped from 5.5% in 2016 to ≤2.0% over the intervention period (June/2016-May/2017) with the pangenotypic intervention, and to ≤3.6% with the Swiss-HCVree-trial. Assuming time to treatment in clinical routine reflected reimbursement restrictions (METAVIR ≥F2, 16.9 years) and stable high-risk behaviour in the overall MSM population, prevalence in 2025 reached 13.1% without intensive intervention, 11.1% with the pangenotypic intervention and 11.8% with the Swiss-HCVree-trial. If time to treatment in clinical routine was 2 years, prevalence in 2025 declined to 4.8% without intensive intervention, to 2.8% with the pangenotypic intervention, and to 3.5% with the Swiss-HCVree-trial. In this scenario, the pangenotypic intervention and the Swiss-HCVree-trial reduced cumulative (2016-2025) treatment episodes by 36% and 24%, respectively. Therefore, intensive interventions could reduce future HCV treatment costs and boost the benefits of long-term efforts to prevent high-risk behaviour and to reduce treatment delay. But if after intensive interventions treatment is deferred until F2, short-term benefits of intensive interventions would dissipate in the long term.

Non-ignorable loss to follow-up: correcting mortality estimates based on additional outcome ascertainment.

Loss to follow-up (LTFU) is a common problem in many epidemiological studies. In antiretroviral treatment (ART) programs for patients with human immunodeficiency virus (HIV), mortality estimates can be biased if the LTFU mechanism is non-ignorable, that is, mortality differs between lost and retained patients. In this setting, routine procedures for handling missing data may lead to biased estimates. To appropriately deal with non-ignorable LTFU, explicit modeling of the missing data mechanism is needed. This can be based on additional outcome ascertainment for a sample of patients LTFU, for example, through linkage to national registries or through survey-based methods. In this paper, we demonstrate how this additional information can be used to construct estimators based on inverse probability weights (IPW) or multiple imputation. We use simulations to contrast the performance of the proposed estimators with methods widely used in HIV cohort research for dealing with missing data. The practical implications of our approach are illustrated using South African ART data, which are partially linkable to South African national vital registration data. Our results demonstrate that while IPWs and proper imputation procedures can be easily constructed from additional outcome ascertainment to obtain valid overall estimates, neglecting non-ignorable LTFU can result in substantial bias. We believe the proposed estimators are readily applicable to a growing number of studies where LTFU is appreciable, but additional outcome data are available through linkage or surveys of patients LTFU.

Supraglottic contributions to pitch raising. Videoendoscopic study with spectroanalysis.

Several questions pertaining to pitch raising recur frequently. Does the larynx rise with the production of higher frequencies? What happens to the pharyngeal walls between the soft palate and the larynx when the fundamental frequency is raised? How does the soft palate participate in pitch raising? To answer these questions, the present study was undertaken with the recently described simultaneous velolaryngeal endoscopy technique. Nine professional singers were asked to find the limits of their vocal range in any of six voice qualities: speech, falsetto, cry/sob, twang, belting, and opera. Simultaneous activities of the larynx, the pharyngeal walls, and the soft palate were submitted to videoendoscopy with synchronous voice recording and studied with spectroanalysis of discrete segments of the total phonation range. Our dual endoscopic study showed that 1) the larynx rose in all subjects with the production of higher frequencies, 2) with the highest fundamental frequency, the lateral pharyngeal walls significantly contracted toward the midline in an "upside-down V shape," creating a very narrow pharyngeal tube, and 3) the soft palate lifted and the velopharyngeal port narrowed considerably with higher frequencies.

Videoendoscopic analysis of laryngeal function during laughter.

Although commonly encountered in all human cultures, laughter remains poorly understood. In order to examine laryngeal function during laughter, telescopic and fiberscopic videolaryngoscopy was performed on five subjects, who laughed in the different vowels, at various frequencies, and in several voice qualities. During laughter, the vocal folds were found consistently to undergo rhythmic abduction and adduction. At the end of these specific phonation tasks, all subjects were able to gain voluntary control of paramedian vocal fold positioning. This study defined laryngeal function during laughter. These results have important clinical implications. Voluntary vocal fold positioning has important applications in speech therapy for dysphonias, such as vocal fold nodules, in which the primary cause is vocal fold hyperadduction. Patients suffering from these hyperadductive dysphonias may be able to utilize laughter to correct them.

Role of the soft palate in laryngeal functions and selected voice qualities. Simultaneous velolaryngeal videoendoscopy.

The role of the soft palate in normal laryngeal functions and in the production of selected voice qualities was studied by a simultaneous velolaryngeal videoendoscopy technique. For this technique, the Olympus ENF-P flexible nasopharyngolaryngoscope was passed via one nostril to study the function of the larynx, while the Hopkins 70 degrees rhinoscopic telescope was passed via the other nostril to study the function of the soft palate and velopharyngeal closure. A Kay Elemetrics DSP Sona-Graph, model 5500, was used to analyze a complex vocal figure of five consecutive voice qualities, three of which were nasal, and two, oral. Simultaneous velolaryngeal videoendoscopy proved to be of great value for the understanding of the interaction of velar and laryngeal functions and for clarifying the mechanisms of nasal and twang qualities.

A framework linkage map of bermudagrass (Cynodon dactylon x transvaalensis) based on single-dose restriction fragments.

This study describes the first detailed linkage maps of two bermudagrass species, Cynodon dactylon (T89) and Cynodon transvaalensis (T574), based on single-dose restriction fragments (SDRFs). The mapping population consisted of 113 F1 progeny of a cross between the two parents. Loci were generated using 179 bermudagrass genomic clones and 50 heterologous cDNAs from Pennisetum and rice. The map of T89 is based on 155 SDRFs and 17 double-dose restriction fragments on 35 linkage groups, with an average marker spacing of 15.3 cM. The map of T574 is based on 77 SDRF loci on 18 linkage groups with an average marker spacing of 16.5 cM. About 16 T89 linkage groups were arranged into four complete and eight into four incomplete homologous sets, while 15 T574 linkage groups were arranged into seven complete homologous sets, all on the basis of multi-locus probes and repulsion linkages. Eleven T89 and three T574 linkage groups remain unassigned. In each parent consensus maps were built based on alignments of homologous linkage groups. Four ancestral chromosomes were inferred after aligning T89 and T574 parental consensus maps using multi-locus probes. The inferred ancestral marker orders were used in comparisons to a detailed Sorghum linkage map using 40 common probes, and to the rice genome sequence using 98 significant BLAST hits, to find regions of colinearity. Using these maps we have estimated the recombinational length of the T89 and T574 genomes at 3,012 and 1,569 cM, respectively, which are 61 and 62% covered by our maps.

Exploratory integration of peanut genetic and physical maps and possible contributions from Arabidopsis.

Arachis hypogaea is a widely cultivated crop both as an oilseed and protein source. The genomic analysis of Arachis species hitherto has been limited to the construction of genetic maps; the most comprehensive one contains 370 loci over 2,210 cM in length. However, no attempt has been made to analyze the physical structure of the peanut genome. To investigate the practicality of physical mapping in peanut, we applied a total of 117 oligonucleotide-based probes ("overgos") derived from genetically mapped RFLP probes onto peanut BAC filters containing 182,784 peanut large-insert DNA clones in a multiplex experimental design; 91.5% of the overgos identified at least one BAC clone. In order to gain insights into the potential value of Arabidopsis genome sequence for studies in divergent species with complex genomes such as peanut, we employed 576 Arabidopsis-derived overgos selected on the basis of maximum homology to orthologous sequences in other plant taxa to screen the peanut BAC library. A total of 353 (61.3%) overgos detected at least one peanut BAC clone. This experiment represents the first steps toward the creation of a physical map in peanut and illustrates the potential value of leveraging information from distantly related species such as Arabidopsis for both practical applications such as comparative map-based cloning and shedding light on evolutionary relationships. We also evaluated the possible correlation between functional categories of Arabidopsis overgos and their success rates in hybridization to the peanut BAC library.