A cluster-randomized trial to reduce major perinatal morbidity among women with one prior cesarean delivery in Québec (PRISMA trial): study protocol for a randomized controlled trial.

BACKGROUND: Rates of cesarean delivery are continuously increasing in industrialized countries, with repeated cesarean accounting for about a third of all cesareans. Women who have undergone a first cesarean are facing a difficult choice for their next pregnancy, i.e.: (1) to plan for a second cesarean delivery, associated with higher risk of maternal complications than vaginal delivery; or (b) to have a trial of labor (TOL) with the aim to achieve a vaginal birth after cesarean (VBAC) and to accept a significant, but rare, risk of uterine rupture and its related maternal and neonatal complications. The objective of this trial is to assess whether a multifaceted intervention would reduce the rate of major perinatal morbidity among women with one prior cesarean. METHODS/DESIGN: The study is a stratified, non-blinded, cluster-randomized, parallel-group trial of a multifaceted intervention. Hospitals in Quebec are the units of randomization and women are the units of analysis. As depicted in Figure 1, the study includes a 1-year pre-intervention period (baseline), a 5-month implementation period, and a 2-year intervention period. At the end of the baseline period, 20 hospitals will be allocated to the intervention group and 20 to the control group, using a randomization stratified by level of care. Medical records will be used to collect data before and during the intervention period. Primary outcome is the rate of a composite of major perinatal morbidities measured during the intervention period. Secondary outcomes include major and minor maternal morbidity; minor perinatal morbidity; and TOL and VBAC rate. The effect of the intervention will be assessed using the multivariable generalized-estimating-equations extension of logistic regression. The evaluation will include subgroup analyses for preterm and term birth, and a cost-effectiveness analysis. DISCUSSION: The intervention is designed to facilitate: (1) women's decision-making process, using a decision analysis tool (DAT), (2) an estimate of uterine rupture risk during TOL using ultrasound evaluation of low-uterine segment thickness, (3) an estimate of chance of TOL success, using a validated prediction tool, and (4) the implementation of best practices for intrapartum management. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN15346559 . Registered on 20 August 2015.

Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis.

OBJECTIVE: To estimate the impact of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin started ≤ 16 weeks' gestation on the prevalence of pre-eclampsia (PE) and the delivery of a small-for-gestational-age (SGA) neonate. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching the medical databases PubMed, EMBASE, Web of Science and Cochrane Central. Pregnant women randomized to receive LMWH or unfractionated heparin in addition to low-dose aspirin were compared with those who received low-dose aspirin alone. Outcome measures were PE, severe PE, early-onset PE and SGA. Pooled relative risks (RRs) with 95% CI were calculated using a random-effects model. RESULTS: Eight RCTs met the inclusion criteria; the indication for recruitment was previous recurrent miscarriage in five studies (three included women with thrombophilia) and a history of severe or early-onset PE in three studies (including women with thrombophilia in one). LMWH was administered in seven studies and unfractionated heparin in one. In women with a history of PE, treatment with LMWH and aspirin, compared with aspirin alone, was associated with a significant reduction in development of PE (three trials (n = 379); RR, 0.54 (95% CI, 0.31-0.92); P = 0.03) and in delivery of SGA neonates (two trials (n = 363); RR, 0.54 (95% CI, 0.32-0.91); P = 0.02). These outcomes were not significantly reduced in women with recurrent miscarriage who received LMWH and aspirin, compared with aspirin alone. The small number of studies precluded sensitivity analyses and the evaluation of publication biases. Blinding to the allocation treatment was absent in all RCTs. CONCLUSIONS: Based on limited evidence, the addition of LMWH to low-dose aspirin could reduce the prevalence of PE and SGA in women with a history of PE. This observation should be the basis of a well-conducted future trial rather than a recommendation for immediate clinical application. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Accuracy of energy expenditure estimation by activity monitors differs with ethnicity.

The aim of this project is to explore the accuracy of 2 activity monitors (SenseWear Armband & Actical) to estimate energy expenditure during rest and light to moderate intensity exercises in 2 ethnic groups. 18 Caucasian and 20 Black adults (age: 26.8±5.2 years; body mass index: 23.9±3.0 kg/m(2)) wore the 2 devices simultaneously during 3 standardised activities: 30-min rest, 45-min of treadmill at 40% of their V˙O2peak and 45-min of stationary cycling at 50% of their V˙O2peak. Energy estimated with the 2 devices was compared to indirect calorimetry measurements. Both devices overestimated energy expenditure during rest (SenseWear: 36% in Black vs. 16% in Caucasian; Actical: 26% vs. 11%, p<0.01 between groups) and treadmill (SenseWear: 50% vs. 25%; Actical: 67% vs. 32%, p<0.01 between groups). Both devices significantly underestimated energy expenditure during stationary cycling (SenseWear: 24% vs. 26%; Actical: 58% vs. 70%, p=NS between groups). Equations used to estimate energy expenditure from accelerometer data is less precise among Black adults than Caucasian adults. Ethnic-specific formulas are probably required.

Surface-enhanced Raman scattering plasmonic enhancement using DNA origami-based complex metallic nanostructures.

DNA origami is a novel self-assembly technique allowing one to form various two-dimensional shapes and position matter with nanometer accuracy. We use DNA origami templates to engineer surface-enhanced Raman scattering substrates. Specifically, gold nanoparticles were selectively placed on the corners of rectangular origami and subsequently enlarged via solution-based metal deposition. The resulting assemblies exhibit "hot spots" of enhanced electromagnetic field between the nanoparticles. We observed a significant Raman signal enhancement from molecules covalently attached to the assemblies, as compared to control nanoparticle samples that lack interparticle hot spots. Furthermore, Raman molecules are used to map out the hot spots' distribution, as they are burned when experiencing a threshold electric field. Our method opens up the prospects of using DNA origami to rationally engineer and assemble plasmonic structures for molecular spectroscopy.

Association between first-trimester placental volume and birth weight.

OBJECTIVE: To estimate the correlation between first-trimester placental volume, birth weight, small-for-gestational-age (SGA), and preeclampsia. METHODS: A prospective study of women with singleton pregnancy at 11-13 weeks of gestation was conducted. First-trimester placental volume was measured using three-dimensional ultrasound and reported as multiple of median (MoM) for gestational age. Participants were followed until delivery where birth weight, placental weight, and occurrence of preeclampsia were collected. Non-parametric analyses were performed. RESULTS: We reached a complete follow-up for 543 eligible women. First-trimester placental volume was significantly correlated with birth weight (correlation coefficient: 0.18; p < 0.0001) and placental weight (cc: 0.22; p < 0.0001) adjusted for gestational age. First-trimester placental volume was smaller in women who delivered SGA neonates (median MoM: 0.79; interquartile range: 0.62-1.00; p < 0.001) and greater in women who delivered large-for-gestational-age neonates (median MoM: 1.13; 0.95-1.49; p < 0.001) when compared to women with neonates between the 10th and 90th percentile (median MoM: 1.00; 0.81-1.25). First-trimester placental volume was not associated with the risk of preeclampsia (cc: 0.01; p = 0.87). CONCLUSION: First-trimester placental volume is strongly associated with fetal and placental growth. However, we did not observe a correlation between placental volume and the risk of preeclampsia.

Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis.

OBJECTIVE: To compare early vs late administration of low-dose aspirin on the risk of perinatal death and adverse perinatal outcome. METHODS: Databases were searched for keywords related to aspirin and pregnancy. Only randomized controlled trials that evaluated the prophylactic use of low-dose aspirin (50-150 mg/day) during pregnancy were included. The primary outcome combined fetal and neonatal death. Pooled relative risks (RR) with their 95% CIs were compared according to gestational age at initiation of low-dose aspirin (≤ 16 vs > 16 weeks of gestation). RESULTS: Out of 8377 citations, 42 studies (27 222 women) were included. Inclusion criteria were risk factors for pre-eclampsia, including: nulliparity, multiple pregnancy, chronic hypertension, cardiovascular or endocrine disease, prior gestational hypertension or fetal growth restriction, and/or abnormal uterine artery Doppler. When compared with controls, low-dose aspirin started at ≤ 16 weeks' gestation compared with low-dose aspirin started at >16 weeks' gestation was associated with a greater reduction of perinatal death (RR = 0.41 (95% CI, 0.19-0.92) vs 0.93 (95% CI, 0.73-1.19), P = 0.02), pre-eclampsia (RR = 0.47 (95% CI, 0.36-0.62) vs 0.78 (95% CI, 0.61-0.99), P < 0.01), severe pre-eclampsia (RR = 0.18 (95% CI, 0.08-0.41) vs 0.65 (95% CI, 0.40-1.07), P < 0.01), fetal growth restriction (RR = 0.46 (95% CI, 0.33-0.64) vs 0.98 (95% CI, 0.88-1.08), P < 0.001) and preterm birth (RR = 0.35 (95% CI, 0.22-0.57) vs 0.90 (95% CI, 0.83-0.97), P < 0.001). CONCLUSION: Low-dose aspirin initiated at ≤ 16 weeks of gestation is associated with a greater reduction of perinatal death and other adverse perinatal outcomes than when initiated at >16 weeks.

Comparison of two different sites of measurement for transabdominal uterine artery Doppler velocimetry at 11-13 weeks.

OBJECTIVES: To compare the feasibility of two transabdominal approaches for performing first-trimester uterine artery (UtA) Doppler and to evaluate the correlation with pulsatility index (PI) in the second trimester. METHODS: This was a prospective longitudinal Doppler study of the uterine arteries at 11-13 and 21-22 weeks' gestation. Transabdominal ultrasound and color Doppler were used to measure the UtA-PI of the ascending branch of the uterine artery at the level of the internal cervical os (Site A) and at the level of the apparent crossover with the external iliac artery (Site B) at 11-13 weeks, and at Site B only at 21-22 weeks. In all cases the measured left and right PI were converted to a multiple of the median (MoM) for gestational age, and the intercorrelation between the measurements at different sites and gestational ages was calculated using non-parametric analysis (Spearman's rank correlation). RESULTS: Satisfactory measurements were obtained at 11-13 weeks from both uterine arteries in all 81 women at Site A and in 50 (62%; 95% CI, 50-72%) at Site B (P < 0.01). Measurements were obtained at Site B at 21-22 weeks in all cases. In the 50 cases with measurements from both sites at 11-13 weeks, the correlation of PI-MoMs between Sites A and B at 11-13 weeks was only moderate (ρ = 0.61). The correlation between first-trimester UtA-PI MoMs at Site A and second-trimester UtA-PI MoMs was stronger than that between first-trimester UtA-PI MoMs at Site B and second-trimester UtA-PI MoMs (ρ = 0.73 vs ρ = 0.47, P < 0.01). CONCLUSION: Evaluation of UtA-PI at 11-13 weeks can be achieved at the level of the internal cervical os in a greater proportion of women than at the level of the apparent crossover with the external iliac vessels, and the measurements obtained correlate better with second-trimester UtA-PI.

Ecotoxicological effects of combined UVB and organic contaminants in coastal waters: A review.

Organisms living in coastal waters are exposed to anthropogenic contaminants from terrestrial drainage, ice melting and maritime traffic and to enhanced UVB radiation (UVBR; 280-320 nm) caused by decreased concentrations of ozone in the stratosphere. This article reviews available information about the combined effects of UVBR and selected hydrosoluble contaminants potentially present in surface waters on marine species and especially on plankton community structure in high-latitude coastal zones. Effects of UVBR on three selected pesticides (Atrazine, carbaryl and Acifluorfen) and possible induction of phototoxicity are reviewed. Most toxicological studies have been conducted under laboratory conditions with questionable relevance for coastal marine ecosystems. Similarly, photoactivation of polycyclic aromatic hydrocarbons (PAHs) has been closely examined and reported effects on aquatic species summarized. Experiments with field-sampled communities demonstrated the complexity and the difficulty in determining the impact of multiple stressors on an aquatic ecosystem, even for ecosystems simplified by eliminating large grazers and fish. Nutrient status, specific composition and light history have influenced the different responses of planktonic assemblages exposed to enhanced UVBR and water-soluble fraction (WSF) from crude oil or to tributyltin. Plankton assemblages subjected to changes in the ozone hole were physiologically stressed and more susceptible to WSF toxicity than communities from less enhanced UVBR-impacted sites. A close relationship between phytoplankton assemblages and bacteria was observed in all experiments in mesocosms. A contaminant-induced phytoplankton crash after a bloom event may release important carbon and nutrient sources for bacteria. The magnitude of phytoplanktonic mortality induced by a contaminant probably influenced how rapidly bacteria grew over time. The transition from a herbivorous food web to a microbial food web has significant ecological implications for carbon cycling and energy flow in pelagic systems. A high phytoplankton mortality implies a situation in which the potential for downward carbon export from surface waters is high. In contrast, high bacterial enrichment implies that the phytoplankton carbon is largely recycled in surface waters through a microbial loop and does not contribute significantly to sinking particle flux. The most ecologically relevant results were obtained with mesocosm studies using field-collected communities. The enhancement of hydrocarbon toxicity in the presence of a high level of UVBR cannot be described as being a synergistic or an additive effect, because the WSF alone is not toxic and may even be beneficial by increasing bacterial activity. This is a case in which one stressor has the ability to modify another stressor to cause it to be toxic to target organisms. These abiotically induced interactions may be important for biological communities exposed to extreme conditions when physical, chemical or photochemical reactions modify the nature of environmental stressors before they interact with biological functions. The need for models on the impacts of multiple stressors on biodiversity and ecosystem functioning is emphasized.

Simulation of ozone depletion using ambient irradiance supplemented with UV lamps.

In studies of the biological effects of UV radiation, ozone depletion can be mimicked by performing the study under ambient conditions and adding radiation with UV-B lamps. We evaluated this methodology at three different locations along a latitudinal gradient: Rimouski (Canada), Ubatuba (Brazil) and Ushuaia (Argentina). Experiments of the effect of potential ozone depletion on marine ecosystems were carried out in large outdoor enclosures (mesocosms). In all locations we simulated irradiances corresponding to 60% ozone depletion, which may produce a 130-1900% increase in 305 nm irradiance at noon, depending on site and season. Supplementation with a fixed percentage of ambient irradiance provides a better simulation of irradiance increase due to ozone depletion than supplementation with a fixed irradiance value, particularly near sunrise and sunset or under cloudy skies. Calculations performed for Ushuaia showed that, on very cloudy days, supplementation by the square-wave method may produce unrealistic irradiances. Differences between the spectra of the calculated supplementing irradiance and the lamp for a given site and date will be a function of the time of day and may become more or less pronounced according to the biological weighting function of the effect under study.

Coding diagnoses and procedures using a high-quality clinical database instead of a medical record review.

A discharge abstract must be completed for each hospitalization. The most time-consuming component of this task is a complete review of the doctors' progress notes to identify and code all diagnoses and procedures. We have developed a clinical database that creates hospital discharge summaries. To compare diagnostic and procedural coding from a clinical database vs. the standard chart review by health records analysts (HRA). All patients admitted and discharged from general medical and surgical services at a teaching hospital in Ontario, Canada. Diagnostic and procedural codes were identified by reviewing discharge summaries generated from a clinical database. Independently, codes were identified by hospital health records analysts using chart review alone. Codes were compared with a gold standard case review conducted by a health records analyst and a doctor. Coding accuracy (percentage of codes in gold standard review) and completeness (percentage of gold standard codes identified). The study included 124 patients (mean length of stay 5.5 days; 66.4% medical patients). The accuracy of the most responsible diagnosis was 68.5% and 62.9% for the database (D) and chart review (C), respectively (P = 0.18). Overall, the database significantly improved the accuracy (D = 78.9% vs. C = 74.5%; P = 0.02) and completeness (D = 63.9% vs. C = 36.7%; P < 0.0001) of diagnostic coding. Although completeness of procedural coding was similar (D = 5.4% vs. C = 64.2%; P = NS), accuracy decreased with the database (D = 70.3% vs. C = 92.2%; P < 0.0001). Mean resource intensity weightings calculated from the codes (D = 1.3 vs. C = 1.4; P = NS) were similar. Coding from a clinical database may circumvent the need for HRAs to review doctors' progress notes, while maintaining the quality of coding in the discharge abstract.

The Responses of a Natural Bacterioplankton Community to Different Levels of Ultraviolet-B Radiation: A Food Web Perspective.

With the continuing increase of ultraviolet-B radiation (UVBR: 280-320 nm) fluxes toward the Earth's surface, there is concern regarding a possible negative impact on heterotrophic bacterioplankton. The effects of enhanced UVBR on a natural bacterioplankton community were studied during a 7-day experiment conducted in mesocosms (1500 L). Four light regimes were tested: natural light, 280 to 313 nm excluded UVBR, and two levels of UVBR enhancement. During the first 3 days of the experiment characterized by high inorganic nutrient concentrations (nitrates > 1 µmol L-1 and ammonium > 0.1 µmol L-l), UVBR had no effect on both bacterial abundances and activities. From day 4 to the end of the experiment, nitrate concentrations remained low (

Overexpressed genes/ESTs and characterization of distinct amplicons on 17q23 in breast cancer cells.

17q23 is a frequent site of gene amplification in breast cancer. Several lines of evidence suggest the presence of multiple amplicons on 17q23. To characterize distinct amplicons on 17q23 and localize putative oncogenes, we screened genes and expressed sequence tags (ESTs) in existing physical and radiation hybrid maps for amplification and overexpression in breast cancer cell lines by semiquantitative duplex PCR, semiquantitative duplex RT-PCR, Southern blot, and Northern blot analyses. We identified two distinct amplicons on 17q23, one including TBX2 and another proximal region including RPS6KB1 (PS6K) and MUL. In addition to these previously reported overexpressed genes, we also identified amplification and overexpression of additional uncharacterized genes and ESTs, some of which suggest potential oncogenic activity. In conclusion, we have further defined two distinct regions of gene amplification and overexpression on 17q23 with identification of new potential oncogene candidates. Based on the amplification and overexpression patterns of known and as of yet unrecognized genes on 17q23, it is likely that some of these genes mapping to the discrete amplicons function as oncogenes and contribute to tumor progression in breast cancer cells.

Bacterial dynamics in first year sea ice and underlying seawater of Saroma-ko Lagoon (Sea of Okhotsk, Japan) and resolute passage (High Canadian Arctic): inhibitory effects of ice algae on bacterial dynamics.

The seasonal development of bacterial abundance in first year bottom ice and underlying seawater were studied at Saroma-ko Lagoon in Hokkaido, Japan, and at Resolute Passage in the High Canadian Arctic during the algal bloom in spring 1992. The aim of this study was to evaluate whether the high algal concentrations reached during the bloom of ice algae have inhibitory effects on bacterial dynamics. Bacterial abundance (measured as total cell count and colony-forming units CFU) increased with the increase of the algal biomass up to 500 micrograms Chla.L-1 in both locations. Culturable fraction (measured as the percentage of CFU counts versus the total cell counts) was between 7% and 22% at Saroma-ko, and approximately 0.08% at Resolute Passage. When algal biomass exceeded 500 micrograms of Chla.L-1, both bacterial abundance and culturable fraction decreased significantly. There was a maximum threshold of algal biomass (between 500 and 800 micrograms of Chla.L-1) after which bacterial dynamics become negatively coupled to the algal biomass. These results suggest that bactericidal and/or bacteriostatic compounds from these extremely high algal concentrations could explain the decrease in bacterial abundance and culturability in bottom ice observed after the ice algae bloom.

Protozoan Bacterivory in the Ice and the Water Column of a Cold Temperate Lagoon.

> Abstract Bacterial abundance and bacterivorous protist abundance and activity were examined in ice-brine and water column communities of a cold temperate Japanese lagoon (Saroma-Ko Lagoon, Hokkaido, 44 degreesN, 144 degreesE), during the late winter phase of ice community development (February-March 1992). Bacterial abundance averaged 6 and 1 x 10(5) cells ml-1 in the ice-brine and plankton samples, respectively, and generally decreased during the sampling period. Bacterivorous protists, identified based on direct observation of short-term (<1 h) ingested fluorescently labeled bacteria (FLB) in their food vacuoles, were largely dominated by flagellates, mainly cryothecomonad-type and chrysomonad-like cells and small dinoflagellates of the genus Gymnodinium. Bacterivorous ciliates included mainly the prostomatid Urotricha sp., the scuticociliates Uronema and Cyclidium, the choreotrichs Lohmaniella oviformis and Strobilidium, and the hypotrich Euplotes sp. Protist abundance averaged 4 x 10(3) and 8.1 cells ml-1 in the ice-brine and 0.3 x 10(3) and 1.2 cells ml-1 in the plankton, for flagellates and ciliates, respectively. In contrast to bacteria, the abundance of protists generally increased throughout the sampling period, indicating predator-prey interactions. Protistan bacterivory, measured from the rate of FLB disappearance over 24 h, averaged 36% (ice) and 24% (plankton) of bacterial standing stock and exhibited the same seasonal pattern as for protist abundance. The calculated specific clearance (range, 2-67 nl protozoa-1 h-1) and ingestion (<1-26 particles protozoa-1 h-1) rates were likely to be minimal estimates and grazing impact may have been higher on occasion. Indications for the dependence of "bacterivorous protists" on nonbacterial food items were also provided. Although alternative sources of bacterial loss are likely to be of importance, this study provides evidence for the potential of protozoan assemblages as bacterial grazers in both sea ice-brine biota and water column at the southern limit of sea ice in the northern hemisphere.

0.25% chlorhexidine gluconate gel. A protective topical microbicide.

BACKGROUND AND OBJECTIVES: An estimated 4 million new cases of chlamydial infection occur each year. This experiment assessed the effects of a vaginally applied gel formulation of 0.25% chlorhexidine gluconate on chlamydial infection and on the vaginal ecosystem. STUDY DESIGN: Twelve monkeys were treated with a single application of 0.25% chlorhexidine gluconate. These animals were assessed for changes in vaginal flora before and at 30 minutes, 1 day, and 2 days postapplication by microbiologic analysis. Cervical and vaginal tissues were assessed by colposcopy at each time point. Five monkeys received a single application of 0.25% chlorhexidine gluconate gel followed (30 minutes) by a cervical inoculation with Chlamydia trachomatis. Four monkeys were inoculated with Chlamydia only. Cervicovaginal tissues were assessed via modified colposcopy, vaginal swabs were collected for assessment of vaginal flora, and cervical swabs were collected for detection of Chlamydia (culture/ligase chain reaction) at baseline and days 1, 2, and 7 postinoculation. RESULTS: Changes in vaginal flora were minimal in all monkeys. Application of 0.25% chlorhexidine gluconate did not affect adversely vaginal colonization by lactobacilli. All chlamydial infection control monkeys were infected, whereas none of the five monkeys pretreated with chlorhexidine gluconate were positive for C. trachomatis by culture or ligase chain reaction. Colposcopic observations remained largely unchanged in all groups. CONCLUSIONS: A 0.25% chlorhexidine gluconate gel was protective against chlamydial infection in all animals tested, had no adverse effect on the vaginal flora, and had minimal effect on cervicovaginal tissues after a single application.

Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis.

Hereditary tyrosinemia type 1 (HT1), a severe inborn error of tyrosine catabolism, is caused by deficiency of the terminal enzyme, fumarylacetoacetate hydrolase (FAH). The highest reported frequency of HT1 is in the French Canadian population, especially in the Saguenay-Lac-St-Jean region. Using human FAH cDNA probes, we have identified 10 haplotypes with TaqI, KpnI, RsaI, BglII, and MspI RFLPs in 118 normal chromosomes from the French Canadian population. Interestingly, in 29 HT1 children, a prevalent haplotype, haplotype 6, was found to be strongly associated with the disease, at a frequency of 90% of alleles, as compared with approximately 18% in 35 control individuals. This increased to 96% in the 24 patients originating from Saguenay-Lac-St-Jean. These results suggest that one or only a few prevailing mutations are responsible for most of the HT1 cases in Saguenay-Lac-St-Jean. Since most patients were found to be homozygous for a specific haplotype in this population, FAH RFLPs have permitted simple carrier detection in nine different informative HT1 families, with a confidence level of 99.9%. Heterozygosity rate values obtained from 52 carriers indicated that approximately 88% of families at risk from Saguenay-Lac-St-Jean are fully or partially informative. Prenatal diagnosis was also achieved in an American family. Analysis of 24 HT1 patients from nine countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association, worldwide, of HT1 with this haplotype.