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PubMed2000

Cost-effectiveness of salmeterol/fluticasone propionate combination product 50/250 microg twice daily and budesonide 800 microg twice daily in the treatment of adults and adolescents with asthma. International Study Group.

Despite a good understanding of the disease and its treatments, asthma continues to place a large economic burden on healthcare systems. As such, it is important to consider the economic impact of alternative therapeutic options for the treatment of this condition to ensure that scarce resources are used in the most efficient manner possible. Thus, the aim of asthma management from an economic perspective is to reduce the burden of this disease through maximizing health gain with available resources. A prospective economic analysis was conducted as part of a multicentre, randomized, double-blind, comparative trial of salmeterol/fluticasone propionate combination product (SFC) 50/250 microg twice daily vs. budesonide (800 microg twice daily) in adults and adolescents with asthma who were symptomatic despite treatment with inhaled corticosteroids at doses of 800-1200 microg day(-1). Treatment effectiveness was measured in terms of successfully-treated weeks, defined as a > or =5% improvement in morning peak expiratory flow, episode-free days (a day without the need for rescue medication, no nocturnal awakening or adverse events) and symptom-free days. Cost-effectiveness analyses were performed using direct healthcare and drug costs, from the perspective of the Swedish healthcare system (1998 prices), with appropriate sensitivity analyses to test the robustness of the findings. Overall, SFC produced significantly higher (P<0.001) proportions of successfully-treated weeks, episode-free days and symptom-free days. Direct asthma management costs were similar between the two groups [SEK19.6 ($US2.4) for SFC vs. SEK18.5 (SUS2.2) for budesonide]. The cost per successfully-treated week was lower for SFC than for budesonide [SEK204 ($US24.8) vs. SEK300 ($US36.4) per week], as were the costs per episode-free day [SEK51.1 ($US6.2) vs. SEK75.1 ($US9.1) per day] and symptom-free day [SEK42.2 ($US5.1) vs. SEK53.0 ($US6.4) per day]. Incremental cost-effectiveness ratios showed that the additional costs to achieve additional benefits with SFC were minimal. Costs per additional successfully-treated week, symptom-free day and episode-free day with SFC were SEK31.6 ($US3.9), SEK9.2 ($US1.1) and SEK7.7 ($US0.9), respectively, relative to budesonide. Sensitivity analysis showed that the results were stable over a wide range of assumptions. The results suggest that SFC is a more cost-effective treatment than budesonide in the management of moderate to severe asthma.

Adult↗
PubMed2005

DNA imaged on a HOPG electrode surface by AFM with controlled potential.

Single-molecule AFM imaging of single-stranded and double-stranded DNA molecules self-assembled from solution onto a HOPG electrode surface is reported. The interaction of DNA with the hydrophobic surface induced DNA aggregation, overlapping, intra- and intermolecular interactions. Controlling the electrode potential and using the phase images as a control method, to confirm the correct topographical characterization, offers the possibility to enlarge the capability of AFM imaging of DNA immobilized onto conducting substrates, such as HOPG. The application of a potential of +300 mV (versus AgQRE) to the HOPG enhanced the robustness and stability of the adsorbed DNA molecules, increasing the electrostatic interaction between the positively charged electrode surface and the negatively charged DNA sugar-phosphate backbone.

Adsorption↗
PubMed2006

Ultra-violet light induced changes in DNA dynamics may enhance TT-dimer recognition.

Short-wave ultra-violet light promotes the formation of DNA dimers between adjacent thymine bases, and if unrepaired these dimers may induce skin cancer. Living cells have a very robust repair system capable of repairing hundreds of lesions every day. Although many of the details of the dimer repair mechanism are known, it is still a mystery how the dimers are recognized. Because the dimers are hidden from repair proteins diffusing in the cell nucleus, it has been surmised that dimer recognition is indirect. In this paper, a new recognition signal is suggested by a theory of the dimer-induced large amplitude, prolonged oscillations in the motion of the two strands in double-stranded DNA molecules. These large amplitude oscillations of the two DNA strands, localized around the dimer will unveil the dimer allowing the repair proteins to bind to the dimer site. The temperature dependence of the recognition rate is correlated with the inter-strand fluctuations and must decrease with decreasing temperature according to the findings in this paper. Moreover the probability for finding a large opening is localized to the dimer neighbourhood and these large openings may play an important role in dimer-repair protein biochemistry.

DNA↗
PubMed2006

Robust, easy, and dose-sensitive methylation test for the diagnosis of Prader-Willi and Angelman syndromes.

We present a new method for differential diagnosis of Prader-Willi (PWS) and Angelman syndromes (AS) that requires only a small amount of DNA including that obtained from amniocentesis specimens. This method not only proved to be robust and rapid, but, most importantly, it can be dosage sensitive, supplying additional information useful for genetic counselling. After methylation-dependent digestion of DNA with HpaII or McrBC, exon 1 of the SNRPN gene is amplified together with a sequence in the CpG island of the H19 gene. Given the similarities in sequence composition and methylation status between the amplified sequences, their co-amplification under semiquantitative conditions allows an easy discrimination between single dosage (present in deletions or chromosomal translocations) and a double-dosage state (uniparental disomy or imprinting error), when the appropriate controls are included. The method we have developed in combination with standard cytogenetic studies and segregation analysis of microsatellite markers offers a rapid and easy procedure to resolve most suspected cases of PWS and AS, and consequently to provide accurate genetic counselling.

Angelman Syndrome↗
PubMed2005

17beta-estradiol supplementation decreases glucose rate of appearance and disappearance with no effect on glycogen utilization during moderate intensity exercise in men.

CONTEXT AND OBJECTIVE: Women use less carbohydrate during endurance exercise, as compared with men. In rodents, 17beta-estradiol (E2) supplementation robustly increases lipid use and lowers muscle and liver glycogen use during exercise. E2 supplementation has been found to influence substrate selection by decreasing glucose rate of appearance (Ra), disappearance (Rd), and metabolic clearance rate during exercise in humans; however, neither a change in total carbohydrate use nor a sparing of muscle glycogen was demonstrated. SUBJECTS AND METHODS: We investigated the effect of 8 d of E2 (2 mg/d) supplementation on glucose turnover and net muscle glycogen use in 11 men using a randomized, double-blind, placebo-controlled, crossover design. Subjects underwent primed constant infusion of [6,6-(2)H]glucose, and muscle biopsies were taken before and after 90 min of cycling at 65% maximal oxygen uptake. RESULTS: E2 supplementation decreased the respiratory exchange ratio (P = 0.03) and glucose Ra and Rd (both P = 0.04) during exercise, as compared with placebo. E2 supplementation lowered proglycogen (P < 0.05) and total glycogen (P = 0.04) concentration, as compared with placebo; however, there was no effect of E2 on net muscle glycogen use during exercise. CONCLUSIONS: These findings show that E2 supplementation alters fuel selection in exercising men by increasing lipid use and reducing carbohydrate use, glucose Ra (primarily liver glucose production), and Rd (primarily muscle glucose uptake). Furthermore, E2 reduces the basal level of total muscle glycogen, particularly the proglycogen form.

Adult↗
PubMed2005

Presentation and analysis of data on radiographic outcome in clinical trials: experience from the TEMPO study.

OBJECTIVE: To evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial. METHODS: A double-blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log-transformed data. RESULTS: Probability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per-protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log-transformed data produced similar results. CONCLUSION: We suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.

Adult↗
PubMed2002

Clinical effects of topiramate against secondarily generalized tonic--clonic seizures.

OBJECTIVE: Intensive and quantitative evaluation of the duration, intensity and frequency of tonic and clonic signs of secondarily generalized tonic-clonic seizures (GTCS) in patients with pharmacoresistant partial seizures during topiramate (TPM) treatment. METHODS: Thirty patients suffering from refractory partial seizures with secondarily GTCS undergoing presurgical evaluation were randomized into a low dosage (100 mg daily) and a parallel medium dosage (200 mg daily) group of TPM add-on medication (15 patients for each group). Study phases included a 3 days baseline video-EEG phase, a 10 days TPM titration phase without video-EEG and a 3 days TPM dose maintenance phase with video-EEG. During the baseline and the dose maintenance phase seizures were recorded using video-EEG monitoring and the following parameters were measured for each recorded secondarily generalized tonic and clonic signs: duration (lasting seconds), intensity (on a 0-3 scale), frequency (numbers per 24 h). RESULTS: A total of 46 complex partial seizures with secondarily generalized tonic-clonic signs during the baseline phase and 20 during the dose maintenance phase were intensively analyzed. More patients in the medium dosage group than in the low dosage groups were free from secondarily GTCS during the dose maintenance phase (nine vs. two, P<0.05). Intergroup comparison suggested that the duration of all tonic signs decreased more in the medium dosage group computing the reduction from baseline to the dose maintenance phase (P<0.05). There were statistically more significant reductions in the duration and intensity of clonic signs in the medium dosage group (P<0.05). CONCLUSION: TPM has an early dose-dependant effect on secondarily GTCS in patients with pharmacoresistant partial seizures. SHORT COMMUNICATION: The present study intensively analyzed the duration, intensity, and frequency of secondarily generalized tonic and clonic signs in patients with pharmacoresistant partial seizures. The quantitative data suggested that TPM had a robust early inhibitory effect on secondarily generalized tonic-clonic signs; effects were more prominent in the medium dosage group (200 mg daily) than in the low dosage group (100 mg daily).

Adolescent↗
PubMed2001

Multiresolution image registration for two-dimensional gel electrophoresis.

In proteomic research, two-dimensional electrophoresis (2-D) is an important tool for investigating differential patterns of qualitative and quantitative protein expression. The strength of the technique is due to its unrivalled power of being able to separate simultaneously thousands of proteins. The key to the comparison of 2-D protein profiles, however, lies in the use of a fast and robust image matching process which is essential to the subsequent quantification procedure. To satisfy the growing demand for a robust and fully automatic method of matching 2-D gel protein separation profiles, we describe in this paper a novel registration technique based on image intensity distribution rather than selected features. The method uses a multiresolution representation of the gel profiles and exploits the fact that coarse approximations to the optimal matching can be extracted efficiently from low-resolution images. This permits the removal of misalignments at different scales in a systematic manner and the strength of the new method has been confirmed by a double blind trial of 111 2-D gel pairs. The proposed method requires neither landmarks nor an a priori image alignment, and takes about five seconds for processing a typical gel pair on a standard personal computer.

Algorithms↗
PubMedDate not supplied

Heterozygosity: an expanding role in proteomics.

The human genome sequence provides the framework for understanding the biology of human cell function. The next step is to intensify the investigation of protein function in the context of complex biological systems. Cellular functions are carried out by molecular complexes acting in concert rather than by single molecules or single reactions. Parallels have been drawn between scale-free nonbiologic networks and functionally interconnected metabolic pathways in the cell. Modeling of metabolic networks, in which functional modules or subnetworks represent individual related pathways, will lead to the prediction of protein function in the larger context of a complex system. Depending on the robustness of these metabolic networks, single-gene defects alone or in combination with other gene defects and the environment have the potential for invoking a spectrum of alterations in the integrity of a given network. The overall purpose of this review is to highlight the importance of simple heterozygosity for one pathogenic mutation or combinatorial heterozygosity for two or more mutations within or between individual genes in altering the stability of metabolic networks. Several forms of heterozygosity are considered, e.g., intra- and interallelic heterozygosity and double heterozygosity. The concepts of synergistic heterozygosity, loss of heterozygosity, and mitochondrial DNA heteroplasmy also are discussed in relation to the quantitative effects of coexisting mutations on the phenotypic expression of disease.

Animals↗
PubMed2006

A meta-analysis of scintimammography: an evidence-based approach to its clinical utility.

BACKGROUND: Scintimammography using (99m)Tc-labelled isonitriles, sestamibi and tetrofosmin, has become a mature technique in the adjunctive setting for the diagnosis of primary breast cancer. To establish an evidence base for its use, clinically, a meta-analysis was performed on both single-site and multi-centre trials performed since January 1997. METHODS: Using an on-line literature search all such trials containing 100 or more studies were identified. To prevent double counting of patients only the last published report from any centre was used. RESULTS: A total of 2424 patients were identified in the single-site trial group, the smallest study having 105 patients and the largest 353 patients. The overall sensitivity was 85% and the specificity was 84%. In the multi-centre trial studies, published data from 3049 patients were included. The overall sensitivity in this group was also 85% and the specificity was 83%. CONCLUSION: There is evidence that this is a robust imaging technique delivering high sensitivities and specificities in patients studied in both single-centre and multi-centre trials and, as such, can be relied on as an adjunctive method for the investigation of primary breast cancer.

Breast Neoplasms↗
PubMed2004

Development and validation of a kinetic assay for analysis of anti-human interleukin-5 monoclonal antibody (SCH 55700) and human interleukin-5 interactions using surface plasmon resonance.

A method to assess the kinetic interactions of a humanized anti-human interleukin-5 (IL-5) monoclonal antibody (SCH 55700) with native human IL-5 using surface plasmon resonance (SPR) has been developed and validated. Since there are no clearly defined validation requirements for a SPR-based binding kinetic assay, the validation strategy was based on the guidelines stipulated by the International Conference on Harmonization for Analytical Method Validation. Due to the uniqueness of the method, however, proper interpretation of the guidance was critical for establishing a validation plan. Validation was designed to assess repeatability, intermediate precision, specificity, linearity, and robustness which included analysis of baseline stability and reproducibility of ligand immobilization. Additionally, system suitability criteria were established to assure that the assay consistently performs as it was intended. The experimental artifacts that can complicate kinetic analysis using biosensor technology, such as heterogeneity of the ligand, mass transport, and nonspecific binding, were considered during the development of this assay. For each run, replicate concentrations of SCH 55700 were injected randomly over the immobilized surfaces to acquire association- and dissociation-phase data. The data were transformed and double referenced to remove systematic deviations seen in the binding responses. Association and dissociation rates were determined using a bivalent analyte model for curve fitting.

Animals↗
PubMed2001

The effects of production and presentation level on the auditory distance perception of speech.

Although both perceived vocal effort and intensity are known to influence the perceived distance of speech, little is known about the processes listeners use to integrate these two parameters into a single estimate of talker distance. In this series of experiments, listeners judged the distances of prerecorded speech samples presented over headphones in a large open field. In the first experiment, virtual synthesis techniques were used to simulate speech signals produced by a live talker at distances ranging from 0.25 to 64 m. In the second experiment, listeners judged the apparent distances of speech stimuli produced over a 60-dB range of different vocal effort levels (production levels) and presented over a 34-dB range of different intensities (presentation levels). In the third experiment, the listeners judged the distances of time-reversed speech samples. The results indicate that production level and presentation level influence distance perception differently for each of three distinct categories of speech. When the stimulus was high-level voiced speech (produced above 66 dB SPL 1 m from the talker's mouth), the distance judgments doubled with each 8-dB increase in production level and each 12-dB decrease in presentation level. When the stimulus was low-level voiced speech (produced at or below 66 dB SPL at 1 m), the distance judgments doubled with each 15-dB increase in production level but were relatively insensitive to changes in presentation level at all but the highest intensity levels tested. When the stimulus was whispered speech, the distance judgments were unaffected by changes in production level and only decreased with increasing presentation level when the intensity of the stimulus exceeded 66 dB SPL. The distance judgments obtained in these experiments were consistent across a range of different talkers, listeners, and utterances, suggesting that voice-based distance cueing could provide a robust way to control the apparent distances of speech sounds in virtual audio displays.

Adult↗
PubMed2005

Individualised cancer therapeutics: dream or reality? Therapeutics construction.

The analysis of DNA microarray and proteomic data, and the subsequent integration into functional expression sets, provides a circuit map of the hierarchical cellular networks responsible for sustaining the viability and environmental competitiveness of cancer cells, that is, their robust systematics. These technologies can be used to 'snapshot' the unique patterns of molecular derangements and modified interactions in cancer, and allow for strategic selection of therapeutics that best match the individual profile of the tumour. This review highlights technology that can be used to selectively disrupt critical molecular targets and describes possible vehicles to deliver the synthesised molecular therapeutics to the relevant cellular compartments of the malignant cells. RNA interference (RNAi) involves a group of evolutionarily conserved gene silencing mechanisms in which small sequences of double-stranded RNA or intrinsic antisense RNA trigger mRNA cleavage or translational repression, respectively. Although RNAi molecules can be synthesised to 'silence' virtually any gene, even if upregulated, a mechanism for selective delivery of RNAi effectors to sites of malignant disease remains challenging. The authors will discuss gene-modified conditionally replicating viruses as candidate vehicles for the delivery of RNAi.

Animals↗
PubMed1996

Cloning and expression of Xenopus CCT gamma, a chaperonin subunit developmentally regulated in neural-derived and myogenic lineages.

The chaperonin containing TCP-1 (CCT) is a eukaryotic cytoplasmic chaperonin, consisting of multiple distinct subunits in a double-toroid structure. In vitro, the CCT has been shown to assist in the folding of tubulin and actin into active conformations through an ATP-dependent mechanism. The function and distribution of these proteins in vivo are also not known. In this report, we show that the expression of two CCT subunits (alpha and gamma) are developmentally regulated in neural-derived and myogenic lineages. While expression in the central nervous system and muscle is consistent with a role in tubulin and actin conformation, we also detect robust expression in the developing cranial neural crest. Enrichment in the neural crest may represent the presence of a novel substrate for the CCT. We have also cloned the complete cDNA for the Xenopus ortholog of CCT gamma, which has 87% amino acid identity with the mouse protein. This remarkable evolutionary conservation suggests a conserved function for this protein among vertebrates, and possibly among all eukaryotes.

Amino Acid Sequence↗
PubMed2006

NKG2A and CD56 are coexpressed on activated TH2 but not TH1 lymphocytes.

NKG2A is commonly expressed on cytotoxic cells but has been found on activated T helper (TH) cells. In identifying novel markers differentiating between TH1 and TH2 lymphocytes, we focused on NKG2A expression. TH1 and TH2 cells were negatively isolated from healthy volunteers for microarray analysis and reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry of quiescent and activated TH1 and TH2 cells was performed. Isolates were >95% pure CD3+CD4+ cells (TH1=90.3% and TH2=84.1%). Microarrays revealed differential expression of NKG2A and NKG2C isoforms between TH1 and TH2 cells. RT-PCR indicated greater expression of NKG2A in TH2 cells (4-fold) and NKG2C in TH1 cells (3-fold). Flow studies revealed tripling of TH2 NKG2A with activation to 10.76+/-4.01% (p=0.05), a 23-fold increase in CD56 to 35+/-14.54% (p=0.03), and an increase in NKG2A+CD56+ double-positive cells to 3.04+/-1.38% (p=0.04). TH1 lymphocytes did not differ with activation. We identified co-induction of NKG2A and CD56 on activation of TH2 cells. These cells would likely bind more HLA-E and exhibit increased effector inhibition. Given that certain viruses are known to decrease MHC class I and thus HLA-E production by antigen-presenting cells, activated TH2 cells would bind less HLA-E in this scenario. This would likely result in less effector inhibition and a relatively robust TH2 response.

Adolescent↗
PubMed2004

Fos expression in the rat brain after intraperitoneal injection of Staphylococcus enterotoxin B and the effect of vagotomy.

The current study was designed to locate the neuronal activation in rat brain following intraperitoneal injection of Staphylococcus enterotoxin B (SEB) and observe the consequence of preliminary subdiaphragmatic vagotomy on SEB-induced brain Fos expression to clarify the role of the vagus nerve in sensation and transmission of abdominal SEB stimulation. The results showed that intraperitoneal SEB (1 mg/kg) induced a robust Fos expression in widespread brain areas. A significant increase of Fos immunoreactive cells were observed in the solitary tract nucleus, locus ceruleus, lateral parabrachial nucleus, ventrolateral part of central gray, medial amygdaloid nucleus, central amygdaloid nucleus, ventromedial part of thalamus, dorsomedial part of thalamus, hypothalamic paraventricular nucleus, lateral habenula, and lateral septum nucleus following SEB challenge. In hypothalamic paraventricular nucleus, in addition to the dense Fos expression in the parvocellular portion, some Fos-positive cells were also observed in the anterior magnocellular nucleus of the complex. Double immunofluorescence studies showed that these Fos-immunoreactive cells were mostly oxytocinergic. The results also showed that subdiaphragmatic vagotomy largely attenuated, but not totally abrogated, the brain Fos expression induced by abdominal administration of SEB. Our data suggest that peripheral SEB stimulation can induce activation of neurons in widespread brain areas and that the vagus plays a crucial role in transmitting the signal of abdominal immune stimulation to the brain.

Animals↗
PubMedDate not supplied

Effect of low oxygen tension on tissue-engineered cartilage construct development in the concentric cylinder bioreactor.

Cartilage is exposed to low oxygen tension in vivo, suggesting culture in a low-oxygen environment as a strategy to enhance matrix deposition in tissue-engineered cartilage in vitro. To assess the effects of oxygen tension on cartilage matrix accumulation, porous polylactic acid constructs were dynamically seeded in a concentric cylinder bioreactor with bovine chondrocytes and cultured for 3 weeks at either 20 or 5% oxygen tension. Robust chondrocyte proliferation and matrix deposition were achieved. After 22 days in culture, constructs from bioreactors operated at either 20 or 5% oxygen saturation had similar chondrocyte densities and collagen content. During the first 12 days of culture, the matrix glycosaminoglycan (GAG) deposition rate was 19.5 x 10(-9) mg/cell per day at 5% oxygen tension and 65% greater than the matrix GAG deposition rate at 20% oxygen tension. After 22 days of bioreactor culture, constructs at 5% oxygen contained 4.5 +/- 0.3 mg of GAG per construct, nearly double the 2.5 +/- 0.2 mg of GAG per construct at 20% oxygen tension. These data demonstrate that culture in bioreactors at low oxygen tension favors the production and retention of GAG within cartilage matrix without adversely affecting chondrocyte proliferation or collagen deposition. Bioreactor studies such as these can identify conditions that enhance matrix accumulation and construct development for cartilage tissue engineering.

Animals↗
PubMed2006

Twinning and risk of stillbirth subtypes in pediatric mothers.

We sought to estimate levels of risk for stillbirth subtypes associated with twin gestations among pediatric mothers (10-14 years). Analysis was on twin pregnancies covering the period 1989 to 2000 in the United States. We classified stillbirth as term, preterm, small-for-gestational-age (SGA) or preterm-SGA. We then assessed the risks of these stillbirth subtypes in pediatric mothers using two comparison groups consisting of women aged 15 to 19 years old (adolescent mothers) and 20 to 24 years old (mature mothers). Adjusted risk estimates were by means of hazard ratios generated from a Cox proportional hazards regression model. We adjusted for dependence of observations within twin clusters using the robust sandwich estimator. The rate of stillbirth was highest among pediatric mothers (56/1000), followed by adolescent gravidas (29/1000) and lowest in mature mothers (20/1000; p for trend < .01). Overall, preterm stillbirth was the most frequent stillbirth phenotype while term stillbirth was the least frequent. Not a single case of term stillbirth was recorded in pediatric mothers. Among pediatric gravidas, the risk for preterm stillbirth was more than tripled (adjusted hazard ratio [AHR] = 3.4; 95% confidence interval [CI] = 2.5-4.6), and that of preterm-SGA stillbirth more than doubled (AHR = 2.6; 95% CI = 1.8-3.7) that of mature mothers respectively. The 30% risk elevation for SGA stillbirth among pediatric mothers was not found to be statistically significant (AHR = 1.1; 95% CI = 0.3-4.3). Pediatric motherhood is a risk factor for stillbirth in twin gestation, especially, preterm and preterm-SGA stillbirth phenotypes. Prevention of stillbirth among this category of mothers should target the period preceding full term.

Adolescent↗