The health and educational costs of preterm birth to 18 years of age in Australia.

BACKGROUND: Preterm birth is the greatest cause of death up to five years of age and an important contributor to lifelong disability. There is increasing evidence that a meaningful proportion of early births may be prevented, but widespread introduction of effective preventive strategies will require financial support. AIMS: This study estimated the economic cost to the Australian government of preterm birth, up to 18 years of age. MATERIALS AND METHODS: A decision-analytic model was developed to estimate the costs of preterm birth in Australia for a hypothetical cohort of 314 814 children, the number of live births in 2016. Costs to Australia's eight jurisdictions included medical expenditures and additional costs to educational services. RESULTS: The total cost of preterm birth to the Australian government associated with the annual cohort was estimated at $1.413 billion (95% CI 1047-1781). Two-thirds of the costs were borne by healthcare services during the newborn period and one-quarter of the costs by educational services providing special assistance. For each child, the costs were highest for those born at the earliest survivable gestational age, but the larger numbers of children born at later gestational ages contributed heavily to the overall economic burden. CONCLUSION: Preterm birth leaves many people with lifelong disabilities and generates a significant economic burden to society. The costs extend beyond those to the healthcare system and include additional educational needs. Assessments of economic costs should inform economic evaluations of interventions aimed at the prevention or treatment of preterm birth.

Reducing preterm birth by a statewide multifaceted program: an implementation study.

BACKGROUND: A comprehensive preterm birth prevention program was introduced in the state of Western Australia encompassing new clinical guidelines, an outreach program for health care practitioners, a public health program for women and their families based on print and social media, and a new clinic at the state's sole tertiary level perinatal center for referral of those pregnant women at highest risk. The initiative had the single aim of safely lowering the rate of preterm birth. OBJECTIVE: The objective of the study was to evaluate the outcomes of the initiative on the rates of preterm birth both statewide and in the single tertiary level perinatal referral center. STUDY DESIGN: This was a prospective population-based cohort study of perinatal outcomes before and after 1 full year of implementation of the preterm birth prevention program. RESULTS: In the state overall, the rate of singleton preterm birth was reduced by 7.6% and was lower than in any of the preceding 6 years. This reduction amounted to 196 cases relative to the year before the introduction of the initiative and the effect extended from the 28-31 week gestational age group onward. Within the tertiary level center, the rate of preterm birth in 2015 was also significantly lower than in the preceding years. CONCLUSION: A comprehensive and multifaceted preterm birth prevention program aimed at both health care practitioners and the general public, operating within the environment of a government-funded universal health care system can significantly lower the rate of early birth. Further research is now required to increase the effect and to determine the relative contributions of each of the interventions.

The elements of success in a comprehensive state-wide program to safely reduce the rate of preterm birth.

BACKGROUND: In 2014, a whole-of-population and multi-faceted preterm birth prevention program was introduced in Western Australia with the single aim of safely lowering the rate of preterm birth. The program included new clinical guidelines, print and social media, and a dedicated new clinic. In the first full calendar year the rate of preterm birth fell by 7.6% and the reduction extended from the 28-31 week gestational age group upwards. OBJECTIVE: The objective of this study was to evaluate outcomes in greater depth and to also include the first three years of the program. STUDY DESIGN: This was a prospective population-based cohort study of perinatal outcomes in singleton pregnancies before and after commencement of the program. RESULTS: There was a significant reduction in preterm birth in the tertiary center which extended from 28 weeks gestation onwards and was ongoing. In non-tertiary centers there was an initial reduction, but this was not sustained past the first year. The greatest reduction was observed in pregnancies classified at first attendance as low risk. No benefit was observed in the private sector, but a significant reduction was seen in the remote region of the Kimberley where the program was first launched and vaginal progesterone had been made free-of-charge. CONCLUSION: Preterm birth rates can be safely reduced by a multi-faceted and whole-of-population program but the effectiveness requires continuing effort and will be greatest where the strategies are most targeted.

Functional topography and integration of the contralateral and ipsilateral retinocollicular projections of ephrin-A-/- mice.

Topographically ordered projections are established by molecular guidance cues and refined by neuronal activity. Retinal input to a primary visual center, the superior colliculus (SC), is bilateral with a dense contralateral projection and a sparse ipsilateral one. Both projections are topographically organized, but in opposing anterior-posterior orientations. This arrangement provides functionally coherent input to each colliculus from the binocular visual field, supporting visual function. When guidance cues involved in contralateral topography (ephrin-As) are absent, crossed retinal ganglion cell (RGC) axons form inappropriate terminations within the SC. However, the organization of the ipsilateral projection relative to the abnormal contralateral input remains unknown, as does the functional capacity of both projections. We show here that in ephrin-A(-/-) mice, the SC contains an expanded, diffuse ipsilateral projection. Electrophysiological recording demonstrated that topography of visually evoked responses recorded from the contralateral superior colliculus of ephrin-A(-/-) mice displayed similar functional disorder in all genotypes, contrasting with their different degrees of anatomical disorder. In contrast, ipsilateral responses were retinotopic in ephrin-A2(-/-) but disorganized in ephrin-A2/A5(-/-) mice. The lack of integration of binocular input resulted in specific visual deficits, which could be reversed by occlusion of one eye. The discrepancy between anatomical and functional topography in both the ipsilateral and contralateral projections implies suppression of inappropriately located terminals. Moreover, the misalignment of ipsilateral and contralateral visual information in ephrin-A2/A5(-/-) mice suggests a role for ephrin-As in integrating convergent visual inputs.

Cone visual pigments in two marsupial species: the fat-tailed dunnart (Sminthopsis crassicaudata) and the honey possum (Tarsipes rostratus).

Uniquely for non-primate mammals, three classes of cone photoreceptors have been previously identified by microspectrophotometry in two marsupial species: the polyprotodont fat-tailed dunnart (Sminthopsis crassicaudata) and the diprotodont honey possum (Tarsipes rostratus). This report focuses on the genetic basis for these three pigments. Two cone pigments were amplified from retinal cDNA of both species and identified by phylogenetics as members of the short wavelength-sensitive 1 (SWS1) and long wavelength-sensitive (LWS) opsin classes. In vitro expression of the two sequences from the fat-tailed dunnart confirmed the peak absorbances at 363 nm in the UV for the SWS1 pigment and 533 nm for the LWS pigment. No additional expressed cone opsin sequences that could account for the middle wavelength cones could be amplified. However, amplification from the fat-tailed dunnart genomic DNA with RH1 (rod) opsin primer pairs identified two genes with identical coding regions but sequence differences in introns 2 and 3. Uniquely therefore for a mammal, the fat-tailed dunnart has two copies of an RH1 opsin gene. This raises the possibility that the middle wavelength cones express a rod rather than a cone pigment.

Trichromacy in Australian marsupials.

Vertebrate color vision is best developed in fish, reptiles, and birds with four distinct cone receptor visual pigments. These pigments, providing sensitivity from ultraviolet to infrared light, are thought to have been present in ancestral vertebrates. When placental mammals adopted nocturnality, they lost two visual pigments, reducing them to dichromacy; primates subsequently reevolved trichromacy. Studies of mammalian color vision have largely overlooked marsupials despite the wide variety of species and ecological niches and, most importantly, their retention of reptilian retinal features such as oil droplets and double cones. Using microspectrophotometry (MSP), we have investigated the spectral sensitivity of the photoreceptors of two Australian marsupials, the crepuscular, nectivorous honey possum (Tarsipes rostratus) and the arhythmic, insectivorous fat-tailed dunnart (Sminthopsis crassicaudata); these species are representatives of the two major taxonomic divisions of marsupials, the diprotodonts and polyprotodonts, respectively. Here, we report the presence of three spectrally distinct cone photoreceptor types in both species. It is the first evidence for the basis of trichromatic color vision in mammals other than primates. We suggest that Australian marsupials have retained an ancestral visual pigment that has been lost from placental mammals.

Applying Precision Public Health to Prevent Preterm Birth.

Preterm birth (PTB) is one of the major health-care challenges of our time. Being born too early is associated with major risks to the child with potential for serious consequences in terms of life-long disability and health-care costs. Discovering how to prevent PTB needs to be one of our greatest priorities. Recent advances have provided hope that a percentage of cases known to be related to risk factors may be amenable to prevention; but the majority of cases remain of unknown cause, and there is little chance of prevention. Applying the principle of precision public health may offer opportunities previously unavailable. Presented in this article are ideas that may improve our abilities in the fields of studying the effects of migration and of populations in transition, public health programs, tobacco control, routine measurement of length of the cervix in mid-pregnancy by ultrasound imaging, prevention of non-medically indicated late PTB, identification of pregnant women for whom treatment of vaginal infection may be of benefit, and screening by genetics and other "omics." Opening new research in these fields, and viewing these clinical problems through a prism of precision public health, may produce benefits that will affect the lives of large numbers of people.

Spectral tuning of the long wavelength-sensitive cone pigment in four Australian marsupials.

The molecular basis for the spectral tuning of longwave-sensitive (LWS) visual pigments in mammals have been described in a wide range of placental species, including the primates. However, little is known about the molecular mechanisms in marsupial LWS pigments. Here, we have studied and compared the LWS opsins in four Australian marsupials: two diprotodonts and two polyprotodonts. Phylogenetic analysis establishes that all LWS marsupial sequences form a distinct clade from the placental mammals that is subdivided into diprotodont and polyprotodont groups. Amino acid sequences reveal that substitutions at sites 277 and 285 are largely responsible for the spectral shifts in marsupial LWS pigments and species comparison indicates that the ancestral gene most likely encoded Tyr277 and Ala180. Amino acid substitutions are discussed in the context of spectral shifts in marsupial LWS and in relation to the mechanisms in primate pigments.

Cone topography and spectral sensitivity in two potentially trichromatic marsupials, the quokka (Setonix brachyurus) and quenda (Isoodon obesulus).

The potential for trichromacy in mammals, thought to be unique to primates, was recently discovered in two Australian marsupials. Whether the presence of three cone types, sensitive to short- (SWS), medium- (MWS) and long- (LWS) wavelengths, occurs across all marsupials remains unknown. Here, we have investigated the presence, distribution and spectral sensitivity of cone types in two further species, the quokka (Setonix brachyurus) and quenda (Isoodon obesulus). Immunohistochemistry revealed that SWS cones in the quokka are concentrated in dorso-temporal retina, while in the quenda, two peaks were identified in naso-ventral and dorso-temporal retina. In both species, MWS/LWS cone spatial distributions matched those of retinal ganglion cells. Microspectrophotometry (MSP) confirmed that MWS and LWS cones are spectrally distinct, with mean wavelengths of maximum absorbance at 502 and 538 nm in the quokka, and at 509 and 551 nm, in the quenda. Although small SWS cone outer segments precluded MSP measurements, molecular analysis identified substitutions at key sites, accounting for a spectral shift from ultraviolet in the quenda to violet in the quokka. The presence of three cone types, along with previous findings in the fat-tailed dunnart and honey possum, suggests that three spectrally distinct cone types are a feature spanning the marsupials.

The rod opsin pigments from two marsupial species, the South American bare-tailed woolly opossum and the Australian fat-tailed dunnart.

Rod visual pigment genes have been studied in a wide range of vertebrates including a number of mammalian species. However, no marsupials have yet been examined. To correct this omission, we have studied the rod pigments in two marsupial species, the nocturnal and frugivorous bare-tailed woolly opossum, Caluromys philander, from Central and South America, and the arhythmic and insectivorous fat-tailed dunnart, Sminthopsis crassicaudata, from Australia. Phylogenetic analysis establishes that the cloned opsin sequences are orthologues of rod opsin genes from other vertebrate species. The deduced amino acid sequences show that both possess glutamate at residue 122, a feature of rod opsins, and the corresponding gene follows the typical vertebrate rod opsin pattern of five exons separated by four introns. Compared to other vertebrates, a stretch of five residues near the C-terminus is deleted in the rod opsin of both marsupials and all eutherian mammals. From microspectrophotometric measurements, the pigments in the two species show an 8 nm difference in peak absorbance; the molecular basis for this spectral shift is discussed and two candidate substitutions are identified.

Strategies to prevent preterm birth.

After several decades of research, we now have evidence that at least six interventions are suitable for immediate use in contemporary clinical practice within high-resource settings and can be expected to safely reduce the rate of preterm birth. These interventions involve strategies to prevent non-medically indicated late preterm birth; use of maternal progesterone supplementation; surgical closure of the cervix with cerclage; prevention of exposure of pregnant women to cigarette smoke; judicious use of fertility treatments; and dedicated preterm birth prevention clinics. Quantification of the extent of success is difficult to predict and will be dependent on other clinical, cultural, societal, and economic factors operating in each environment. Further success can be anticipated in the coming years as other research discoveries are translated into clinical practice, including new approaches to treating intra-uterine infection, improvements in maternal nutrition, and lifestyle modifications to ameliorate maternal stress. The widespread use of human papillomavirus vaccination in girls and young women will decrease the need for surgical interventions on the cervix and can be expected to further reduce the risk of early birth. Together, this array of clinical interventions, each based on a substantial body of evidence, is likely to reduce rates of preterm birth and prevent death and disability in large numbers of children. The process begins with an acceptance that early birth is not an inevitable and natural feature of human reproduction. Preventative strategies are now available and need to be applied. The best outcomes may come from developing integrated strategies designed specifically for each health-care environment.

Retinal photoreceptor arrangement, SWS1 and LWS opsin sequence, and electroretinography in the South American marsupial Thylamys elegans (Waterhouse, 1839).

We studied the retinal photoreceptors in the mouse opossum Thylamys elegans, a nocturnal South American marsupial. A variety of photoreceptor properties and color vision capabilities have been documented in Australian marsupials, and we were interested to establish what similarities and differences this American marsupial showed. Thylamys opsin gene sequencing revealed two cone opsins, a longwave-sensitive (LWS) opsin and a shortwave-sensitive (SWS1) opsin with deduced peak sensitivities at 560 nm and 360 nm (ultraviolet), respectively. Immunocytochemistry located these opsins to separate cone populations, a majority of LWS cones (density range 1,600-5,600/mm(2)) and a minority of SWS1 cones (density range 100-690/mm(2)). With rod densities of 440,000-590,000/mm(2), the cones constituted 0.4-1.2% of the photoreceptors. This is a suitable adaptation to nocturnal vision. Cone densities peaked in a horizontally elongated region ventral to the optic nerve head. In ventral-but not dorsal-retina, roughly 40% of the LWS opsin-expressing cones occurred as close pairs (double cones), and one member of each double cone contained a colorless oil droplet. The corneal electroretinogram (ERG) showed a high scotopic sensitivity with a rod peak sensitivity at 505 nm. At mesopic light levels, the spectral ERG revealed the contributions of a UV-sensitive SWS1 cone mechanism and an LWS cone mechanism with peak sensitivities at 365 nm and 555 nm, respectively, confirming the tuning predictions from the cone opsin sequences. The two spectral cone types provide the basis for dichromatic color vision, or trichromacy if the rods contribute to color processing at mesopic light levels.

Cone visual pigments in two species of South American marsupials.

Marsupials are largely confined to Australasia and to Central and South America. The visual pigments that underlie the photosensitivity of the retina have been examined in a number of species from the former group where evidence for trichromatic colour vision has been found, but none from the latter. In this paper, we report the cone opsin sequences from two nocturnal South American marsupial species, the gray short-tailed opossum, Monodelphis domestica, and the big-eared opossum, Didelphis aurita. Both are members of the Order Didelphimorphia (American opossums). For both species, only two classes of cone opsin were found, an SWS1 and an LWS sequence, and in vitro expression showed that the peak sensitivity of the SWS1 pigment is in the UV. Analysis of the Monodelphis genome confirms the absence of other classes of cone visual pigment genes. The SWS1 and LWS genes with 4 and 5 introns respectively, show the same exon-intron structure as found for these genes in all other vertebrates. The SWS1 gene shows a conserved synteny with flanking genes. The LWS gene is X-linked, as in all therian mammals so far examined, with a locus control region 1.54 kb upstream.

The ecology of visual pigment tuning in an Australian marsupial: the honey possum Tarsipes rostratus.

While most mammals have no more than two types of cone photoreceptor, four species of Australian marsupial have recently been shown to possess three types, and thus have the potential for trichromatic colour vision. Interestingly, the long-wave cones of the honey possum Tarsipes rostratus are tuned to longer wavelengths than those of the other species measured to date. We tested whether the honey possum's long-wave tuning is adaptive for visual tasks associated with its almost unique diet of nectar and pollen. We modelled three tasks: (1) detecting food-rich 'target' flowers against their natural background of foliage or other vegetation; (2) discriminating target flowers from flowers of non-target species; (3) discerning the maturity of the most important target flowers. Initial comparisons of trichromacy vs dichromacy generally favoured the former, but interestingly dichromacy was no disadvantage in some cases. For tuning, we found that overall the honey possum's long-wave tuning is more adaptive than that of the other marsupial species. Nevertheless, the optimal tuning for tasks 1 and 2 would be at longer wavelengths still, implying that a different pressure or constraint operates against a further long-wave shift of the honey possum's L cone tuning. Our data show that a possible ecological pressure may be provided by the third task--the difficult and potentially critical discrimination of the maturity of the animal's major food supply, the flowers of Banksia attenuata.