Income, egalitarianism and attitudes towards healthcare policy: a study on public attitudes in 29 countries.

OBJECTIVES: To evaluate the relationship between income and egalitarian values and attitudes towards healthcare policy. STUDY DESIGN: Cross-sectional and cross-national study. METHODS: Data for 29 countries from the International Social Survey Programme (ISSP) 2011 were used. The dependent variables are a general attitude towards government involvement in healthcare provision and two attitudes regarding specific policies (taxes and public funding). Income and egalitarianism were also measured by using ISSP. Data were analysed using regression models that account for individual and country-level characteristics, and country-fixed effects. RESULTS: The effect of income is small and non-significant for attitudes towards government involvement and public funding. For willingness to pay (WTP) taxes to improve healthcare services, we find a positive association with income. Results for egalitarianism suggest a positive association with government involvement in healthcare provision and significant interactions with WTP taxes. CONCLUSIONS: The distinction of dimensions and mechanisms underlying policy attitudes appears as relevant. Citizens across socioeconomic groups are motivated to support state-funded healthcare, favouring the design of non-selfish policies. These findings suggest that there is space for policymakers who seek to increase healthcare spending encouraging either policies for specific groups or broader institutional changes.

Use of emerging technologies in the extraction of lupeol, α-amyrin and ß-amyrin from sea grape (Coccoloba uvifera L.).

Emerging technologies are being explored to improve extraction yields of phytochemicals or high-value biological compounds. The aim of this study was to evaluate the extraction of lupeol, α-, and ß-amyrin from fruit, leaf and stem of the sea grape tree (Coccoloba uvifera L.) using technologies such as Ultrasound Assisted Extraction (UAE) and High Hydrostatic Pressure Extraction (HHPE). Results were compared to conventional extraction (maceration). Analysis with thin-layer chromatography revealed the presence of lupeol in all studied parts of the tree. Optimal extraction conditions for UAE and HHPE were found; the highest concentration of triterpenes was obtained by UAE after evaluating conventional and non-conventional techniques. Finally, analysis of different tree parts and other vegetable sources showed that the best source of triterpenes was the leaf.

Micronized natural progesterone (Seidigestan®) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.

Introduction: Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome. Methods: We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes. Discussion: The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors. Clinical trial registration: ClinicalTrials.gov, identifier, NCT05954962.

[Diagnosis of neurocysticercosis in patients with epilepsy living in the south-western Dominican Republic]. / Diagnóstico de neurocisticercosis en pacientes con epilepsia residentes en el suroeste de la República Dominicana.

INTRODUCTION: Neurocysticercosis (NCC), a possible cause of epilepsy with limited epidemiological data in the Dominican Republic, is endemic in four provinces in the country's south-western region. This study aimed to determine the association between NCC and epilepsy among people living in these endemic regions, and to obtain preliminary data on the prevalence of NCC in these provinces. PATIENTS AND METHODS: A case-control design was used, consisting of 111 patients with epilepsy with unknown causes, and 60 controls without epilepsy or NCC. The diagnosis of NCC was based on computed tomography and magnetic resonance imaging of the skull, as well as Western immunoblotting for serum antibodies using Taenia solium, following the criteria of Del Brutto et al. RESULTS. NCC was found in 27% of the epileptic patients (n = 30/111) and in 5% of the controls (n = 3/60); the probability of the epileptic patients having NCC was seven times higher than the controls (odds ratio = 7.04, 95% confidence interval: 2.04-24.18; p < 0.001). The participants' sociodemographic characteristics, including their age, sex, level of education, occupation, and province of residence presented no statistical significance in terms of their association with NCC. CONCLUSIONS: This study suggests that NCC is strongly associated with epilepsy in the south-western region of the Dominican Republic, and highlights the need for public health measures to improve the prevention, diagnosis and treatment of both diseases.

TITLE: Diagnóstico de neurocisticercosis en pacientes con epilepsia residentes en el suroeste de la República Dominicana.Introducción. La neurocisticercosis (NCC), una posible causa de epilepsia con datos epidemiológicos limitados en la República Dominicana, es endémica en cuatro provincias de la región suroeste. El objetivo de este estudio fue determinar la asociación entre la NCC y la epilepsia en personas que viven en estas regiones endémicas, así como obtener datos preliminares sobre la prevalencia de NCC en estas provincias. Sujetos y métodos. Se utilizó un diseño de casos y controles compuesto por 111 pacientes con epilepsia de causa desconocida y 60 controles sin epilepsia ni NCC. El diagnóstico de NCC se basó en la tomografía computarizada y la resonancia magnética del cráneo, así como en el inmunotransferencia de Western para anticuerpos séricos contra Taenia solium, siguiendo los criterios de Del Brutto et al. Resultados. Se encontró NCC en el 27% de los pacientes con epilepsia (n = 30/111) y en el 5% de los controles (n = 3/60); los casos de epilepsia tenían siete veces más probabilidades de tener NCC que los controles (odds ratio = 7,04, intervalo de confianza al 95%: 2,04-24,18; p < 0,001). Las características sociodemográficas de los participantes, como la edad, el sexo, el nivel de escolaridad, la ocupación y la provincia de residencia no mostraron significación estadística en cuanto a la asociación con NCC. Conclusiones. Este estudio sugiere que la NCC está fuertemente asociada con la epilepsia en la región suroeste de la República Dominicana, y destaca la necesidad de medidas de salud pública para mejorar la prevención, el diagnóstico y el tratamiento de ambas enfermedades.

Serum IL-12 is increased in Mexican obese subjects and associated with low-grade inflammation and obesity-related parameters.

Interleukin-(IL-) 12 has been recently suggested to participate during development of insulin resistance in obese mice. Nevertheless, serum IL-12 levels have not been accurately determined in overweight and obese humans. We thus studied serum concentrations of IL-12 in Mexican adult individuals, examining their relationship with low-grade inflammation and obesity-related parameters. A total of 147 healthy individuals, 43 normal weight, 61 overweight, and 43 obese subjects participated in the study. Circulating levels of IL-12, tumor necrosis factor-alpha (TNF- α ), leptin, insulin, glucose, total cholesterol, and triglyceride were measured after overnight fasting in all of the study subjects. Waist circumference and body fat percentage were recorded for all the participants. Serum IL-12 was significantly higher in overweight and obese individuals than in normal weight controls. Besides being strongly related with body mass index (r = 0.5154), serum IL-12 exhibited a significant relationship with abdominal obesity (r = 0.4481), body fat percentage (r = 0.5625), serum glucose (r = 0.3158), triglyceride (r = 0.3714), and TNF- α (r = 0.4717). Thus, serum levels of IL-12 are increased in overweight and obese individuals and show a strong relationship with markers of low-grade inflammation and obesity in the Mexican adult population. Further research is needed to understand the role of IL-12 in developing obesity-associated alterations in humans.

Semi-automatic Sono T measurement of nuchal translucency.

A prospective study of 63 singleton pregnancies between 11 + 0 and 13 + 6 weeks gestation underwent semi-automatic nuchal translucency (NT) measurement and were compared with two-dimensional ultrasonography (2D US). Inter-observer variation and the repeatability were evaluated. Sono T automatically achieves mid-sagittal plane views and measures the maximum NT thickness. Measurements have less inter-observer variation (CI = -0.13, -0.04) when compared with 2D measurements (CI = -0.45, 0.28). It is reproducible and comparable to conventional 2D US technique for NT measurement. However, incorporating Sono T into routine practice requires further program refinements in order to reduce erroneous NT measurements.

Triggering with GnRH agonist in oocyte-donation cycles: oestradiol monitoring is not necessary during ovarian stimulation.

This prospective observational study evaluated the efficacy and safety of oocyte-donation cycles triggered with a gonadotrophin-releasing hormone (GnRH) agonist without monitoring oestradiol concentrations during ovarian stimulation. A total of 97 oocyte donors received recombinant FSH (150-225/day) and GnRH antagonists (0.25mg/day). Oocyte maturation was triggered with 0.2mg triptorelin s.c. Donors aged 25.4 ± 4.1 years were stimulated for 8.8 ± 0.9 days and underwent 2.9 ± 0.5 (2-4) ultrasound assessments. Total FSH dose was 1703.4 ± 304.7IU, antagonists were administered for 4.3 ± 1.0 days, 14.7 ± 8.8 oocytes were retrieved and there were no cases of ovarian hyperstimulation syndrome. Recipients (n=123) aged 40.3 ± 3.4 years received 10.9 ± 4.3 oocytes, 88.7% of which were metaphase II. Intracytoplasmic sperm injection fertilization rate was 79% and 2.18 ± 0.6 (1-3) embryos were transferred. The pregnancy, clinical pregnancy and twin pregnancy rates were 64.2%, 57.7% and 19.7%, respectively. In conclusion, given the high efficacy and safety of the GnRH-antagonist protocol triggered with a GnRH agonist, the monitoring of oestradiol concentrations is not necessary. Ultrasound monitoring is enough for an adequate follow up of the stimulation cycle in oocyte donors.

Predicting ovarian reserve and reproductive outcome using antimüllerian hormone (AMH) and antral follicle count (AFC) in patients with previous assisted reproduction technique (ART) failure.

PURPOSE OF INVESTIGATION: The main objective of our prospective, observational, analytical research work was to determine whether Anti-Müllerian hormone (AMH) and antral follicle count (AFC) could be effectively used as predictors of ovarian reserve and, possibly, of reproductive outcome with ART. METHODS: We studied 143 IVF/ET cycles in patients with a previous history of ART failure, all of them supposed to be of poor prognosis, who had agreed to another ART attempt after knowing their AMH, AFC, and base hormone (FSH, LH, 17 beta-estradiol) levels. RESULTS: AMH and AFC showed a positive correlation with the number of oocytes retrieved (p = 0.0016) and (p < 0.0001), respectively and with percentage of MII oocytes, (p = 0.00756) and (p < 0.001). The combined use of these markers showed an area under the curve of 82.2% for oocytes retrieved. Our results shows a very high cancelation (22% of started cycles) and very low pregnancy rates (6.7% and 9.8%) in low and normoresponders, respectively. CONCLUSIONS: AMH levels and AFC are reliable indicators of ovarian reserve. Patients with ovarian reserve levels that predict a very low probability of success should be informed that the poor prognosis associated with these values may not justify the expense of IVF/ET.

Work-related traumatic spinal cord lesions in Chile, a 20-year epidemiological analysis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe the characteristics of patients with work-related traumatic spinal cord injuries (TSCI) in Chile. SETTING: Hospital del Trabajador in Santiago, Santiago, Chile. METHODS: Patients suffering from TSCI incurred at the workplace from 1986 to 2005 were identified through records of the Asociación Chilena de Seguridad (ACHS, Chilean Safety Association). RESULTS: The medical records of 173 patients, 172 men and 1 woman, were analyzed. The yearly average incidence was 7.8 per million workers. Age at TSCI onset was 38.2 ± 12.1 years. The principal external causes for TSCI incurred at the workplace were falls from a height in 86 cases (49.7%) and trauma blows to the vertebral spine in 61 cases (35.3 %). More falls occurred in the field construction, and other traumas occurred as a result of traumatic blows caused by tree trunks and stones in forestry and mining sectors. Mortality in this series was 8.7%, and the worst prognosis was for older patients with complete tetraplegia. The paraplegia:tetraplegia ratio was 3.2:1. CONCLUSIONS: The characteristics of workplace TSCI are specific to this population. It is important therefore to develop prevention programs for specific work-related TSCI.

Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support.

The aim of this study in patients at risk of ovarian hyperstimulation syndrome (OHSS) was to determine the efficacy and safety of luteal support using human chorionic gonadotrophin (HCG) after triggering ovulation with gonadotrophin-releasing hormone (GnRH) agonist in IVF/intracytoplasmic sperm injection antagonist cycles. A total of 192 OHSS-risk patients, following a GnRH antagonist protocol (0.25mg/day cetrorelix) during recombinant FSH stimulation, were triggered with 1.5mg s.c. leuproreline for ovulation. A total of three boluses of HCG were used for luteal support, 1000IU (group A, n=44), 500IU (group B, n=115) or 250IU (group C, n=33) every third day, starting the day after oocyte retrieval. For the reproductive outcome, main variables were biochemical and clinical pregnancy rates, and for OHSS, the variables were the numbers of moderate and severe OHSS cases. Overall pregnancy rate was 51.8% and clinical pregnancy rate was 43.4%. This study observed eight cases of moderate (4.2%) and seven of severe OHSS (3.6%). Six out of the seven (85.7%) severe cases were late-onset OHSS, related to pregnancy. In conclusion, GnRH agonist single dose for triggering ovulation and low doses of HCG used as luteal-phase support seem to secure a normal pregnancy outcome without increasing the OHSS risk.

High doses of GnRH antagonists are efficient in the management of severe ovarian hyperstimulation syndrome.

OBJECTIVE: To determine whether treatment of severe ovarian hyperstimulation syndrome (OHSS) with high-dose gonadotropin-releasing hormone (GnRH) antagonist, due to its luteolytic effect, is an effective method of management. METHODS: Six infertile patients who had been scheduled for embryo transfer and developed early-onset severe OHSS with ascites and hemoconcentration were chosen for treatment with 3.0 mg of a GnRH antagonist (Cetrotide; Cetrorelix, Serono, Madrid, Spain). The response of these patients was compared with five patients with severe early-onset OHSS who received support therapy alone. All patients were evaluated clinically, echographically, and hematologically. RESULTS: Estradiol (E2) levels dropped significantly a few days after treatment. Peritoneal fluid regression measured by ultrasound was faster on the study group compared with controls. Hematocrit remained comparable in both groups during follow-up. In two cases a second bolus of GnRH-antagonist was used due to clinical and biochemical findings during the four days of observation following the initial dose. None of the patients treated with GnRH antagonists required paracentesis. CONCLUSIONS: Treatment with high doses of GnRH antagonists seems to be effective in the management of severe OHSS.

Novel Insights Into the Role of Glycans in the Pathophysiology of Glomerular Endotheliosis in Preeclampsia.

The polysaccharide heparan sulfate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. In the glomerular filtration barrier, the action of the heparan sulfate is directly related to the function of glomerular filtration, mostly attributed to the sulfated domains that occur along the polysaccharide chain, as evidenced by fact that release of fragments of heparan sulfate by heparanase significantly increases the permeability of albumin passage through the glomerular endothelium, event that originates proteinuria. This review aims to show the importance of the structural domains of heparan sulfate in the process of selective permeability and to demonstrate how these domains may be altered during the glomerular inflammation processes that occur in preeclampsia.

Behaviour of health professionals concerning the recommendations for prophylaxis for infectious endocarditis in our setting: Are the guidelines followed? / Conducta de los profesionales sanitarios ante las recomendaciones de profilaxis de endocarditis infecciosa en nuestro medio: ¿se siguen las guías?

OBJECTIVES: The prophylaxis regimens for infectious endocarditis recommended by the clinical practice guidelines have recently changed. We do not know whether the current regimens are correctly followed in our setting. Our objective was to describe the approaches of various health professionals concerning these guidelines. MATERIAL AND METHODS: We conducted a survey in Cordoba, using a 16-item online questionnaire on this topic. We randomly selected a sample of 180 practitioners (20 cardiologists, 80 dentists and 80 primary care physicians), of whom 173 responded. RESULTS: Half of the participants were men; 52% had more than 20 years of professional experience. Some 88.3% of the participants considered that prophylaxis of endocarditis is effective (77.8% of the cardiologists, 93.7% of the dentist; p=.086). In general, prophylaxis is performed in conditions of clearly established risk (>90% of those surveyed). However, prophylaxis is also performed in a high proportion of cases with no risk of endocarditis, varying between 30 and 60% according to the procedure (mostly the dentists, between 36 and 67%, followed by the primary care physicians, between 28 and 59%). The antibiotic regimens employed varied significantly. The primary care physicians were furthest from the recommended regimen (only 25.8% used the recommended regimen vs. 54.4% of dentists and 72.2% of cardiologists; p=.002). CONCLUSIONS: Compliance with the recommendations on prophylaxis for endocarditis should be improved in our setting. We observed a tendency, especially among noncardiologists, to "overindicate" the prophylaxis.

Characterization of hemocytes from the mosquitoes Anopheles gambiae and Aedes aegypti.

Hemocytes are an essential component of the mosquito immune system but current knowledge of the types of hemocytes mosquitoes produce, their relative abundance, and their functions is limited. Addressing these issues requires improved methods for collecting and maintaining mosquito hemocytes in vitro, and comparative data that address whether important vector species produce similar or different hemocyte types. Toward this end, we conducted a comparative study with Anopheles gambiae and Aedes aegypti. Collection method greatly affected the number of hemocytes and contaminants obtained from adult females of each species. Using a collection method called high injection/recovery, we concluded that hemolymph from An. gambiae and Ae. aegypti adult females contains three hemocyte types (granulocytes, oenocytoids and prohemocytes) that were distinguished from one another by a combination of morphological and functional markers. Significantly more hemocytes were recovered from An. gambiae females than Ae. aegypti. However, granulocytes were the most abundant cell type in both species while oenocytoids and prohemocytes comprised less than 10% of the total hemocyte population. The same hemocyte types were collected from larvae, pupae and adult males albeit the absolute number and proportion of each hemocyte type differed from adult females. The number of hemocytes recovered from sugar fed females declined with age but blood feeding transiently increased hemocyte abundance. Two antibodies tested as potential hemocyte markers (anti-PP06 and anti-Dox-A2) also exhibited alterations in staining patterns following immune challenge with the bacterium Escherichia coli.

Novel antagonists of 5-HT3 receptors. Synthesis and biological evaluation of piperazinylquinoxaline derivatives.

A series of piperazinylquinoxalines has been synthesized and studied as 5-HT3 receptor antagonists in different preparations. Antagonism to 5-HT in the longitudinal muscle of the guinea pig ileum was particularly prominent in cyanoquinoxaline derivatives with an alkyl substitutuent on the piperazine moiety. The pA2 of some selected compounds against the 5-HT3 agonist 2-methyl-5HT in the guinea pig ileum was in the range of tropisetron or ondansetron, and one of them, 7e, was more potent than these reference compounds by approximately 2 or 3 orders of magnitude. However, these compounds were markedly less potent than either tropisetron or ondansetron as displacers of 3H-BRL 43694 binding to rat cortical membranes or as antagonists of the Bezold-Jarisch reflex in rats. Piperazinylcyanoquinoxalines represent a new class of 5-HT3 antagonists with a selective effect on guinea pig peripheral receptors.

New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants.

In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.

Simple and complex stent strategies for bifurcated coronary arterial stenosis involving the side branch origin.

Coronary lesions located in major bifurcations constitute a challenge for the use of stents. Although the occlusion of a side branch covered by a stent is infrequent, the maintenance of a patent, stenosis-free bifurcation may result in a complex procedure. Between September 1994 and April 1998, 70 patients were treated by stent implantation for coronary bifurcation stenosis. The side branch always had a diameter >2 mm. The pairs of treated arteries were: left anterior descending (LAD)/diagonal artery in 32 patients, circumflex/obtuse marginal in 26, right coronary/posterior descending artery in 5, and LAD/circumflex in 7. We applied 2 different techniques of stent implantation: (1) deployment of 1 stent in the parent vessel covering the takeoff of the side branch and subsequent angioplasty of the side branch across the metallic structure (group A, n = 47 patients), and (2) implantation of 1 stent at the ostium of the side branch and complete reconstruction of the entire bifurcation with additional implantation of 1 or 2 stents at the parent vessel (group B, n = 23 patients). There were no significant differences between groups at baseline variables. Procedural success was similar in both groups: 42 (89%) in group A versus 21 (91%) in group B. However, major cardiac events at 18 months follow-up were higher in group B (event-free probability 44% vs 75%, p <0.05). Selected patients with coronary stenosis at major bifurcations can be treated with an acceptable rate of primary and late success. Complex techniques providing radical stent reconstruction of the bifurcation seems to provide no advantages over the simpler stent jail followed by ostial side branch balloon dilation.

New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.