Real-world outcomes of unrestricted direct-acting antiviral treatment for hepatitis C in Australia: The South Australian statewide experience.

In March 2016, the Australian government offered unrestricted access to direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) to the entire population. This included prescription by any medical practitioner in consultation with specialists until sufficient experience was attained. We sought to determine the outcomes and experience over the first twelve months for the entire state of South Australia. We performed a prospective, observational study following outcomes of all treatments associated with the state's four main tertiary centres. A total of 1909 subjects initiating DAA therapy were included, representing an estimated 90% of all treatments in the state. Overall, SVR12 was 80.4% in all subjects intended for treatment and 95.7% in those completing treatment and follow-up. 14.2% were lost to follow-up (LTFU) and did not complete SVR12 testing. LTFU was independently associated with community treatment via remote consultation (OR 1.50, 95% CI 1.04-2.18, P = .03), prison-based treatment (OR 2.02, 95% CI 1.08-3.79, P = .03) and younger age (OR 0.98, 95% CI 0.97-0.99, P = .05). Of the 1534 subjects completing treatment and follow-up, decreased likelihood of SVR12 was associated with genotype 2 (OR 0.23, 95% CI 0.07-0.74, P = .01) and genotype 3 (OR 0.23, 95% CI 0.12-0.43, P ≤ .01). A significant decrease in treatment initiation was observed over the twelve-month period in conjunction with a shift from hospital to community-based treatment. Our findings support the high responses observed in clinical trials; however, a significant gap exists in SVR12 in our real-world cohort due to LTFU. A declining treatment initiation rate and shift to community-based treatment highlight the need to explore additional strategies to identify, treat and follow-up remaining patients in order to achieve elimination targets.

Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward.

BACKGROUND: Hepatitis C treatment is successful in 40-80% of patients in drug sponsored registration trials. However, few studies have examined treatment outcomes in non-trial, routine clinical practice settings. AIM: The aim of this study was to investigate the treatment outcomes and predictors of a sustained virological response in a routine clinical setting. METHODS: Data were collected retrospectively on patients treated for hepatitis C between January 2004 and March 2010 in a tertiary hospital setting. Demographics, treatment outcomes and potential predictors of outcome (viral genotype, viral load, virological response, platelet count, alanine transaminase level, glucose, ferritin, weight, fibrosis and cirrhosis, compliance, dose reductions, adverse events, psychiatric and alcohol history) were recorded. Univariate and multiple logistic regressions were performed. RESULTS: A total of 405 patients was treated during the study period. On an intention to treat basis, sustained virological response rates were 55%, 82% and 72% in genotypes 1, 2 and 3 respectively. Predictors of response were gender, age, genotype, weight, fibrosis, cirrhosis, platelet count and alanine transaminase on univariate analysis. Age, genotype, cirrhosis and platelet count were independently associated with sustained virological response on multiple logistic regression. CONCLUSION: In our cohort, treatment outcomes for genotype 1 and 2 were similar to results from clinical trials but results for genotype 3 were inferior. Clinicians should not assume that results from registration trials are transferable to their own clinical practice. This has particular relevance for the new era of triple therapy regimens containing direct antivirals.

Independent adaptation to riverine habitats allowed survival of ancient cetacean lineages.

The four species of "river dolphins" are associated with six separate great river systems on three subcontinents and have been grouped for more than a century into a single taxon based on their similar appearance. However, several morphologists recently questioned the monophyly of that group. By using phylogenetic analyses of nucleotide sequences from three mitochondrial and two nuclear genes, we demonstrate with statistical significance that extant river dolphins are not monophyletic and suggest that they are relict species whose adaptation to riverine habitats incidentally insured their survival against major environmental changes in the marine ecosystem or the emergence of Delphinidae.

Molecular phylogenetic examination of the delphinoidea trichotomy: congruent evidence from three nuclear loci indicates that porpoises (Phocoenidae) share a more recent common ancestry with white whales (Monodontidae) than they do with true dolphins (Delphinidae).

Porpoises (Phocoenidae), dolphins (Delphinidae), and the two species of Monodontidae (beluga and narwhal) together constitute the superfamily Delphinoidea. Although there is extensive evidence supporting the monophyly of this superfamily, previous studies involving morphology, as well as sequence analysis of mitochondrial genes, have failed to yield a clear picture of the relative relationships within the group. Here we present the first examination of this issue from the perspective of single-copy nuclear genes at the DNA sequence level. The data involve three such loci: von Willebrand factor (vWF), interphotoreceptor retinoid binding protein (IRBP), and lactalbumin. The vWF and IRBP data sets consist of protein-coding fragments, whereas the sequenced lactalbumin fragment is predominately intronic. All phylogenetic analyses involving at least one representative from each of the three Delphinoidea families congruently support a beluga/porpoise clade. The levels of sequence divergence for most of these data appear to roughly concur with a paleontological date for the radiation of the Delphinoidea at 11-15 MYA but, in agreement with mitochondrial DNA sequence analyses, suggest that the extant major groups of cetaceans radiated approximately 25 MYA, 10 million years later than inferred from paleontological data.

Stability of cladistic relationships between Cetacea and higher-level artiodactyl taxa.

Over the past 10 years, the phylogenetic relationships among higher-level artiodactyl taxa have been examined with multiple data sets. Many of these data sets suggest that Artiodactyla (even-toed ungulates) is paraphyletic and that Cetacea (whales) represents a highly derived "artiodactyl" subgroup. In this report, phylogenetic relationships between Cetacea and artiodactyls are tested with a combination of 15 published data sets plus new DNA sequence data from two nuclear loci, interphotoreceptor retinoid-binding protein (IRBP) and von Willebrand factor (vWF). The addition of the IRBP and vWF character sets disrupts none of the relationships supported by recent cladistic analyses of the other 15 data sets. Simultaneous analyses support three critical clades: (Cetacea + Hippopotamidae), (Cetacea + Hippopotamidae + Ruminantia), and (Cetacea + Hippopotamidae + Ruminantia + Suina). Perturbations of the combined matrix show that the above clades are stable to a variety of disturbances. A chronicle of phylogenetic results over the past 3 years suggests that cladistic relationships between Cetacea and artiodactyls have been stable to increased taxonomic sampling and to the addition of more than 1,400 informative characters from 15 data sets.

Molecular evidence for multiple origins of Insectivora and for a new order of endemic African insectivore mammals.

The traditional views regarding the mammalian order Insectivora are that the group descended from a single common ancestor and that it is comprised of the following families: Soricidae (shrews), Tenrecidae (tenrecs), Solenodontidae (solenodons), Talpidae (moles), Erinaceidae (hedgehogs and gymnures), and Chrysochloridae (golden moles). Here we present a molecular analysis that includes representatives of all six families of insectivores, as well as 37 other taxa representing marsupials, monotremes, and all but two orders of placental mammals. These data come from complete sequences of the mitochondrial 12S rRNA, tRNA-Valine, and 16S rRNA genes (2.6 kb). A wide range of different methods of phylogenetic analysis groups the tenrecs and golden moles (both endemic to Africa) in an all-African superordinal clade comprised of elephants, sirenians, hyracoids, aardvark, and elephant shrews, to the exclusion of the other four remaining families of insectivores. Statistical analyses reject the idea of a monophyletic Insectivora as well as traditional concepts of the insectivore suborder Soricomorpha. These findings are supported by sequence analyses of several nuclear genes presented here: vWF, A2AB, and alpha-beta hemoglobin. These results require that the order Insectivora be partitioned and that the two African families (golden moles and tenrecs) be placed in a new order. The African superordinal clade now includes six orders of placental mammals.

Highly congruent molecular support for a diverse superordinal clade of endemic African mammals.

A solution to higher level mammalian phylogeny is going to depend on the congruent establishment of superordinal groupings followed by a linking together of these clades. We present congruent and convincing evidence from four disparate nuclear protein coding genes and from a tandem alignment of the 12S-16S mitochondrial region, for a superordinal clade of endemic African mammals that includes elephant shrews, aardvarks, golden mole, elephants, sirenians, and hyraxes. Because of strong support for golden mole as part of this clade, the Insectivora are rendered paraphyletic or polyphyletic, with constrained monophyly of the insectivores judged significantly worse in the vast majority of tests. Branching arrangement within this clade remains highly uncertain; however, a tandem alignment of the protein coding genes suggests elephant shrew is the earliest African lineage. None of the individual data sets or combinations of data sets support the widely held view of a mirorder Tethytheria (Sirenia/Proboscidea), although only a tandem alignment of protein coding and mitochondrial loci significantly rejects this association. The majority of the data sets and analyses provide strong support for Caviomorpha as part of a monophyletic Rodentia.

Endemic African mammals shake the phylogenetic tree.

The order Insectivora, including living taxa (lipotyphlans) and archaic fossil forms, is central to the question of higher-level relationships among placental mammals. Beginning with Huxley, it has been argued that insectivores retain many primitive features and are closer to the ancestral stock of mammals than are other living groups. Nevertheless, cladistic analysis suggests that living insectivores, at least, are united by derived anatomical features. Here we analyse DNA sequences from three mitochondrial genes and two nuclear genes to examine relationships of insectivores to other mammals. The representative insectivores are not monophyletic in any of our analyses. Rather, golden moles are included in a clade that contains hyraxes, manatees, elephants, elephant shrews and aardvarks. Members of this group are of presumed African origin. This implies that there was an extensive African radiation from a single common ancestor that gave rise to ecologically divergent adaptive types. 12S ribosomal RNA transversions suggest that the base of this radiation occurred during Africa's window of isolation in the Cretaceous period before land connections were developed with Europe in the early Cenozoic era.

The interphotoreceptor retinoid binding protein gene in therian mammals: implications for higher level relationships and evidence for loss of function in the marsupial mole.

The subclass Theria of Mammalia includes marsupials (infraclass Metatheria) and placentals (infraclass Eutheria). Within each group, interordinal relationships remain unclear. One limitation of many studies is incomplete ordinal representation. Here, we analyze DNA sequences for part of exon 1 of the interphotoreceptor retinoid binding protein gene, including 10 that are newly reported, for representatives of all therian orders. Among placentals, the most robust clades are Cetartiodactyla, Paenungulata, and an expanded African clade that includes paenungulates, tubulidentates, and macroscelideans. Anagalida, Archonta, Altungulata, Hyracoidea + Perissodactyla, Ungulata, and the "flying primate" hypothesis are rejected by statistical tests. Among marsupials, the most robust clade includes all orders except Didelphimorphia. The phylogenetic placement of the monito del monte and the marsupial mole remains unclear. However, the marsupial mole sequence contains three frameshift indels and numerous stop codons in all three reading frames. Given that the interphotoreceptor retinoid binding protein gene is a single-copy gene that functions in the visual cycle and that the marsupial mole is blind with degenerate eyes, this finding suggests that phenotypic degeneration of the eyes is accompanied by parallel changes at the molecular level as a result of relaxed selective constraints.

Mammalian evolution and the interphotoreceptor retinoid binding protein (IRBP) gene: convincing evidence for several superordinal clades.

Phylogenetic relationships of 25 mammalian species representing 17 of the 18 eutherian orders were examined using DNA sequences from a 1.2-kb region of the 5' end of exon 1 of the single-copy nuclear gene known as interphotoreceptor retinoid binding protein (IRBP). A wide variety of methods of analysis of the DNA sequence, and of the translated products, all supported a five-order clade consisting of elephant shrew (Macroscelidea)/aardvark (Tubulidentata)/and the paenungulates (hyracoids, sirenians, and elephants), with bootstrap support in all cases of 100%. The Paenungulata was also strongly supported by these IRBP data. In the majority of analyses this monophyletic five-order grouping was the first branch off the tree after the Edentata. These results are highly congruent with two other recent sources of molecular data. Another superordinal grouping, with similar 100% bootstrap support in all of the same wide-ranging types of analyses, was Artiodactyla/Cetacea. Other superordinal affinities, suggested by the analyses, but with less convincing support, included a Perissodactyla/Artiodactyla/Cetacea clade, an Insectivora/Chiroptera clade, and Glires (an association of rodents and lagomorphs).

Trends in caesarean section in Western Australia, 1980-1987.

During the 1980s the incidence of both emergency and elective caesarean section in Western Australia increased, accompanied by a decrease in that of all other delivery methods. The proportion of emergency caesarean sections increased from 5.9%. of all deliveries in 1980 to 8.2% in 1987 and that of elective sections from 5.3% to 8.7%. For each year studied less than 50% of primiparous women delivering singletons had a normal vaginal delivery. Emergency caesarean sections were more common in primiparas and at the teaching hospital and elective sections in multiparas and at the metropolitan private hospitals. The proportion of primiparas having either emergency or elective caesarean sections rose with maternal age, but for multiparas the proportion having elective sections rose, but there were few differences in emergency sections with increasing age. Repeat caesarean sections, which made up 28.8% of the total in 1987, have contributed increasingly to the rising proportion of caesarean section deliveries. Unless the number of emergency sections in primiparous women falls and the challenge of vaginal birth after caesarean section is met, it is likely that the caesarean section rate in Western Australia will continue to increase over the next decade.

Stillbirths in Western Australia 1980-1983: influence of race, residence and place of birth.

All stillbirths in Western Australia from 1980-83 weighing 1,000 g and over were identified from perinatal death certificates, and their causes and demographic correlates described. The stillbirth rate was 4.91 per 1,000 total births; nearly 65% were antepartum, 25% intrapartum and in 10% the time of death was unknown. The cause of death of most stillbirths was unknown (52%) or associated with lethal congenital malformations (13%), antepartum haemorrhage (12%) or maternal hypertension (8%). Whilst Aboriginal women had much higher stillbirth rates (10.80) than non-Aboriginal women (4.57), their patterns of time and causes of death were similar. Both antepartum and intrapartum stillbirth rates were much higher at low birth-weights and low gestational ages in both racial groups. Women living in rural areas who delivered in the metropolitan area had much higher antepartum (11.02) and intrapartum (3.31) stillbirth rates than either rural women delivering in rural areas (1.89 and 1.34) or metropolitan women delivering in the metropolitan area (2.72, 0.98). This reflects the transfer of rural high risk pregnant women or those with fetal death in utero, for delivery in metropolitan specialist hospitals.

Variation in hospital morbidity in the male workforce of Western Australia.

The associations of hospital morbidity with occupation were studied in Western Australian men of working age in 1981-2. Data on hospital morbidity were derived from a population based system that covered all short stays in hospitals in the state. Occupations were grouped into 12 major categories and conditions were coded using the International Classification of Diseases. Armed services personnel had the highest overall rate of hospital admissions, followed by transport and communications workers and by administrative and managerial workers. Injuries were the most common cause of referral to hospital. Four occupational groups, farmers and allied workers, miners and quarrymen, transport and communications workers, and craftsmen, production workers, and labourers were often associated with injury. Diseases of the musculoskeletal system and connective tissue were the second most common cause for referral and were increased in transport and communications workers, and in craftsmen, production workers, and labourers. Several other associations between causes of hospital admission and major occupational groups were observed, including associations of circulatory system diseases with professional and technical work and with administrative and managerial work. The excess of hospital admissions due to factors associated with occupation was estimated to be 12,665 admissions a year or 24.9% of the total in working men.

Changing patterns of perinatal and infant mortality in Western Australia: implications for prevention.

Perinatal and infant mortality rates have fallen dramatically in the developed world this century. A review of perinatal and infant mortality in Western Australia from 1970 to 1981 was undertaken, to examine trends in birthweight-specific and cause-specific rates. The predominant causes of death are now congenital malformation, stillbirth of unknown cause, preterm birth and cot death. Perinatal and infant mortality rates are unlikely to be reduced substantially until the reasons for these four causes of death are elucidated.

PIP: Stillbirth, neonatal, and postneonatal infant deaths in Western Australia were analyzed from 1970 to 1981. Falls in all 3 rates were apparent. The neonatal mortality rate showed the sharpest decline, from 14.05 to 5.47/1000 total births. The stillbirth rate dropped from 12.64 to 8.31, and the postneonatal infant mortality rate fell from 6.24 to 2.27. The intrapartum stillbirth rate for nonmalformed fetuses of over 28 weeks gestation fell from 2.55 in 1970 to 0.68 in 1981. The largest percentage of stillbirths, 37% in both 1970 and 1981, was associated with birthweight under 1000 gm. Congenital malformation as a cause of neonatal death doubled from 20.9% in 1970 to 39.2% in 1981. In the postneonatal period, crib death accounted for 35.2% of deaths in 1970 and 51.9% in 1981. Recent improvements in perinatal and infant mortality are attributed to better obstetric and pediatric services as well as the introduction of neonatal intensive care units. 4 conclusions are drawn from these findings: 1) the major causes of perinatal and infant deaths--congenital malformations, stillbirths of unknown cause, preterm births, and crib death--should be investigated further; 2) given the current low levels of mortality, further improvements in health care cannot be expected to generate additional dramatic declines, and the task is to develop indices of perinatal morbidity as measures of care and to identify problem areas; 3) prevention of preterm births and malformation has the potential to reduce both morbidity and mortality; and 4) declines in community-based factors such as standard of living, immunization coverage, and access to medical care are certain to have a negative effect on infant mortality rates.

Specifying morphological factors affecting rates of death due to malignant neoplasms.

This paper reports research which examines the relations between select social morphological factors of population size and density and rates of death due to malignant neoplasms among males and females within countries in the north-east and west regions of the U.S.A. between 1960 and 1970. Generally it was found that populations having a stable morphological structure have a negative relation with rates of death due to malignant neoplasms; populations experiencing a change in population morphology, particularly an increase in the number of persons per housing unit, have a positive relation with rates of death due to malignant neoplasms. The importance of tapping different dimensions of the spatial environment is illustrated as future research on the social epidemiology of malignant neoplasms is suggested.