In vitro Validation of Quantitative Light-Induced Fluorescence for the Diagnosis of Enamel Fluorosis in Permanent Teeth.

This study aimed to validate quantitative light-induced fluorescence (QLF) as a diagnostic tool for mild and moderate enamel fluorosis in permanent teeth, comparing it to visual diagnosis and histological assessment completed using polarized light microscopy (PLM). The buccal surfaces of 139 teeth were visually classified using the Thylstrup and Fejerskov Index (TFI) into sound (TFI 0; n = 17), mild (TFI 1-2; n = 69), and moderate (TFI 3-4; n = 43) fluorosis. Fluorosis was then assessed with QLF (variables ΔF, A, and ΔQ at 5-, 15-, and 30-radiance thresholds) using as reference areas the entire surface and a region of interest (ROI), identified as the most representative region of a fluorosis lesion. PLM images of longitudinal thin sections including the ROI were assessed for histological changes. Correlations among TFI, PLM, and QLF were determined. A receiver-operating characteristic curve was conducted to determine QLF's diagnostic accuracy when compared to the TFI and PLM assessments. This was used to assess the probability that the images were correctly ranked according to severity as determined by PLM and TFI. A positive correlation was found between QLF and PLM, and between QLF and TFI. QLF showed the highest sensitivity and specificity for the diagnosis of mild fluorosis. There was also a strong agreement between TFI and PLM. The selection of a ROI resulted in a stronger correlation with TFI and PLM than when the entire surface was used. The study results indicate that defining an ROI for QLF assessments is a valid method for the diagnosis of mild and moderate enamel fluorosis.

Reproductive and population parameters of spiny dogfish Squalus acanthias in the south-western Atlantic Ocean.

The objective of this study was to estimate reproductive and population parameters of the spiny dogfish Squalus acanthias for the south-western Atlantic Ocean. In total, 2714 specimens (1616 males and 1098 females) were collected from surveys carried out using research vessels. Males ranged from 225 to 861 mm total length (LT ) and females from 235 to 925 mm LT . The size at maturity of females (651 mm) was significantly greater than that of males (565 mm). The maximum proportion of mature individuals (Pmax ) of the gestation ogive was <1, which indicates that a proportion of mature females was not in gestation. This inactivity may be explained by the occurrence of resting periods between cycles or by the asynchrony of the reproductive cycle. The estimated Pmax for the maternity ogive suggested that about one third of mature females were in the maternity stage (i.e. with embryos >156 mm). The temporal and spatial co-occurrence of non-gravid adult females at different stages of ovarian development, as well as gravid females at all embryonic development stages would indicate that the female reproductive cycle in the south-western Atlantic Ocean is asynchronous. The results indicate that S. acanthias is susceptible to fishing pressure on account of its length at maturity, extended reproductive cycles and low fecundity.

Trophic ecology of yellownose skate Zearaja chilensis, a top predator in the south-western Atlantic Ocean.

The diet and trophic level (TL ) of the yellownose skate Zearaja chilensis in the south-western Atlantic Ocean (35°-54° S), and how these varied in relation to body size, sex, maturity stage, depth and region were determined by analysis of stomach contents. From 776 specimens analysed, 671 (86·5%) ranging from 180 to 1190 mm total length (LT ) had prey in their stomachs. The diet was dominated by fishes, mainly the notothenioid Patagonotothen ramsayi and the Argentine hake Merluccius hubbsi. The consumption of fishes and crabs increased with increasing predator size, and these preys were more important in the north than in the south. Isopods and other crustaceans were consumed more in the south and their consumption decreased as the size of Z. chilensis increased. The TL of Z. chilensis increased with LT from 4·29 to 4·59 (mean 4·53), confirming their ecological role as a top predator. The small and large size classes exhibited a low diet overlap and the highest spatial segregation, whereas medium and large specimens had higher co-occurrence and dietary overlap indices. A clear distinction in tooth shape was noted between sexes in adult specimens, with males having longer cusps. This sexual heterodonty may be related to reproductive behaviour, increasing the grasping ability of males during courtship, because there were no differences in diet between the sexes.

Fish diversity in the Río de la Plata and adjacent waters: an overview of environmental influences on its spatial and temporal structure.

The fish diversity and the main environmental factors affecting the spatial distribution of species, life history stages and community structure in the Río de la Plata (RdP) and adjacent waters are reviewed and analysed, with emphasis on the functional guild classification. The functional guild classification indicated that most species in the RdP were marine stragglers, zoobenthivores and oviparous species, although the biomass was dominated by estuarine species. Salinity had a stronger influence than temperature on the spatial pattern for all life stages, shallower and fresher waters are the preferred habitats of neonates and juveniles. During the breeding season (spring-summer), adults showed an intrusion into the inner part of RdP or to its adjacent nearshore waters from the offshore waters for spawning or mating, respectively. Variations in river discharge and wind patterns greatly affected the spatial extent of estuarine water, which ultimately influenced the domain of the main life-history stages (juveniles or adults) for both marine and estuarine fishes, as well as species and fish assemblage composition. The strong environmental gradient restricts some species and life-history stages to a particular section and defines three main fish assemblage areas. The composition of the fish assemblage is indicative of the recruitment of freshwater and marine species to the estuary in opposite ways, determined by the vertical stratification. Seasonal changes in the species composition were related to migration as a result of salinity and temperature variations and reproductive migrations to spawning and mating areas. This overview reveals that the RdP is under environmental variations that are likely to produce modifications to fish distribution and abundance that affect its fisheries. This context plus fish stock declines and changes in exploitation patterns could amplify the magnitude of the variations in the fisheries resources availability and affect the sustainability of fishing communities.

COVID-19 pandemic on coronary artery and cerebrovascular diseases in Southern Spain: interrupted time series analysis.

OBJECTIVE: Healthcare systems have been put under intense pressure by the COVID-19 pandemic, although some studies have shown a decline in hospital admissions for cardiovascular and cerebrovascular diseases during the first and second wave of the pandemic. In addition, studies analyzing gender and procedural differences are scarce. The present study aimed to determine the impact of the pandemic on hospital admissions for acute myocardial infarction (AMI) and cerebrovascular disease (CVD) in Andalusia (Spain) and analyzed differences by gender and by percutaneous coronary interventions performed. PATIENTS AND METHODS: An interrupted time series analysis of AMI and CVD hospital admissions in Andalusia (Spain) was carried out to measure the impact of the COVID-19 outbreak. AMI and CVD cases admitted daily in public hospitals of Andalusia between January 2018 and December 2020 were included. RESULTS: During the pandemic, significant reductions in AMI [-19%; 95% confidence interval (CI): (-29%, -9%), p<0.001] and CVD [-17%; 95% CI: (-26%, -9%); p<0.01] in daily hospital admissions were observed. Differences were also produced according to the diagnosis (ST-Elevation Myocardial Infarction, Non-ST-Elevation Myocardial Infarction, other AMI and stroke), with a greater reduction in females for AMI and in males for CVD. Although there were more percutaneous coronary interventions during the pandemic, no significant reductions were observed. CONCLUSIONS: A decline in AMI and CVD daily hospital admissions during the first and second wave of COVID-19 pandemic was noted. Gender differences were observed, but no clear impact was observed in percutaneous interventions.

Axon reflexes evoked by transient receptor potential vanilloid 1 activation are mediated by tetrodotoxin-resistant voltage-gated Na+ channels in intestinal afferent nerves.

Capsaicin-sensitive nerves mediate axon vasodilator reflexes in the intestine, but the ion channels underlying action potential (AP) propagation are poorly understood. To examine the role of voltage-gated Na(+) channels underlying these reflexes, we measured vasomotor and electrophysiological responses elicited by capsaicin in guinea pig and mouse dorsal root ganglia (DRG) neurons, submucosal arterioles, and mesenteric arteries in vitro. Transient receptor potential vanilloid 1 (TRPV1) agonists dilated guinea pig ileal submucosal arterioles and were blocked by capsazepine and ruthenium red. In double-chamber baths, capsaicin-evoked activation of TRPV1 on proximal perivascular nerves in the left chamber evoked dilations of the distal segment of the submucosal arteriole in the right chamber. Dilations were tetrodotoxin (TTX) (1 microM)-resistant, but reducing extracellular Na(+) (10% solution) or applying the Na(v) 1.8 antagonist A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide] (1 microM) in the proximal chamber blocked capsaicin-evoked dilations in the distal chamber (88%; P = 0.01 and 75% and P < 0.02, respectively). In mouse mesenteric arteries, electrical field stimulation and capsaicin (2 microM) evoked dilations that were also TTX-resistant. In perforated patch-clamp recordings, APs in mouse and guinea pig capsaicin-sensitive DRG neurons were TTX-resistant but blocked by 10% extracellular Na(+). When capsaicin-evoked AP conduction was studied in in vitro ileal multiunit afferent nerve preparations, capsaicin responses were elicited in the presence of TTX, whereas distention-evoked responses were almost completely blocked by TTX. Together, these data provide evidence for TTX-resistant AP conduction in extrinsic sensory neurons that innervate guinea pig and mouse intestine and suggest this neural propagation is sufficient to mediate axon reflexes in the intestine.

Is eating wild rainbow trout safe? The effects of different land-uses on heavy metals content in Chile.

Cu, Mn, Fe, Zn, Cd and Pb levels were measured in liver and muscle samples of Rainbow Trout Oncorhynchus mykiss collected from three watersheds with different land-uses: native forest, exotic plantation, and agriculture in Chile, during January, April, July, and October 2012. Cd and Pb levels were not detected in the liver and muscle, probably since they are under the detection limits. Higher metal concentrations (liver-muscle tissues) were detected in samples from agriculture and exotic plantation streams, whereas trout from native forest streams had lower metal concentrations. Higher metal concentrations were detected in liver tissue compared to muscle tissue, and both negatively correlated to the length and weight of the fish. This suggest the liver had higher ability to accumulate Cu, Mn, Fe and Zn compared to muscle tissue. The concentration range of Fe and Zn recorded in the muscle are within the range reported by other authors, whereas Mn and Cu concentrations are higher than reported in the literature. However, at all sites the concentration of selected metals were below the limits permitted by current legislation (FAO), and therefore did not put the human population at risk, suggesting that is eating wild rainbow trout safe in Chile.

Factors associated with uninvestigated dyspepsia in students at 4 Latin American schools of medicine: A multicenter study. / Factores asociados a dispepsia no investigada en estudiantes de 4 facultades de medicina de Latinoamérica: estudio multicéntrico.

INTRODUCTION AND AIMS: Dyspepsia is a multifactorial disease that can involve alcohol, tobacco, or nonsteroidal anti-inflammatory drug use, as well as lifestyle, diet, socioeconomic elements, or psychologic factors. The aim of the present article was to establish the frequency of uninvestigated dyspepsia and determine its associated factors in students at 4 Latin American schools of medicine. MATERIALS AND METHODS: A cross-sectional, analytic study was conducted, in which a survey made up of closed-ended questions was applied at just one point in time. The association between the variables was then analyzed. A new questionnaire for the diagnosis of dyspepsia was one of the tests utilized to diagnose uninvestigated dyspepsia. Generalized linear models were used for the bivariate and multivariate analyses, employing the Poisson model with the log link function, obtaining crude prevalence ratios, adjusted prevalence ratios, and their 95% confidence intervals. RESULTS: Of the 1,241 individuals surveyed, 54% (841) were females and the median age was 21 years (range: 19-23 years). Prevalence of uninvestigated dyspepsia was 46%. The factors that had a direct association with dyspepsia were: depression, difficulty sleeping, and coffee consumption. On the contrary, eating regularly in a boarding house and the male sex had an inverse association. CONCLUSIONS: Uninvestigated dyspepsia frequency was high in students at 4 Latin American schools. Depression, difficulty sleeping, and steady coffee drinking were factors directly associated with dyspepsia, whereas male sex and eating out at regular hours were factors with a reverse association. Therefore, we recommend that universities implement early detection programs for this highly preventable pathology.

Un cuerpo extraño inusual de cianoacrilato en el oído. Presentación de un caso clínico y revisión de la literatura / An unusual cyanoacrylate foreign body in the ear. Presentation of a clinical case and literature review

El pegamento basado en cianoacrilato posee una gran capacidad de adherencia a los tejidos, representando un problema cuando se encuentra en el oído externo debido a sus características anatómicas particulares. Se presenta un caso clínico de cuerpo extraño de cianoacrilato que ocluye el conducto auditivo externo y el tímpano, alterando la audición. Se describen los hallazgos y los intentos de extracción utilizando las alternativas terapéuticas descritas en la literatura, sin obtener resultados positivos, debiendo recurrir a la extracción quirúrgica. Además, se presentan detalles del procedimiento y los resultados. El paciente recupera la audición y la normalidad anatómica.

Cyanoacrylate-based glue has a great capacity for adhering to tissue, which is a problem when it is placed in the ear canal due to the anatomy of this structure. A clinical case of a cyanoacrylate foreign body occluding the external auditory canal and the tympanic membrane is presented. The therapeutics alternatives described in the literature used in the case failed, so, it was surgically removed by drilling the glue. Details of the procedure and results are presented. The patient recovers the hearing and anatomical normality.

Enfermedad de Castleman unicéntrica, una causa infrecuente de masa cervical / Unicentric Castleman disease, an infrequent cause of cervical mass

La enfermedad de Castleman (EC) describe una serie de desórdenes linfoproliferativos de patrones histológicos similares, pero de etiologías, presentaciones clínicas y enfrentamientos notoriamente variables. Se presenta el caso de un paciente que consultó por masa cervical, cuyo estudio final concluyó EC unicéntrica, la cual se resolvió de forma quirúrgica. Además, se presenta una revisión actualizada del tema, con foco en la enfermedad unicéntrica.

Castleman's disease (CD) describes several lymphoproliferative disorders with similar histological patterns, but with notoriously variable etiologies, clinical presentations, and management. We present the case of a patient who consulted with cervical mass, whose final study concluded with unicentric CD, which was treated surgically. In addition, an updated review of the subject is presented, focusing on unicentric disease.

Barotrauma inducido por vuelo en otorrinolaringología: Una revisión de la literatura

Barotrauma se define como el daño tisular generado por diferencias de presión entre un espacio no ventilado dentro del cuerpo y el gas o fluido circundante. La causa más frecuente de barotrauma es el viaje en avión y se espera un aumento progresivo de los casos en el tiempo. Los órganos habitualmente comprometidos son el oído, cavidades paranasales y nervio facial. La fisiopatología del barotrauma por vuelo se fundamenta en la exposición a cambios bruscos de altitud y presión asociados a infecciones respiratorias altas y/o disfunción de la tuba auditiva. Los síntomas más frecuentes son otalgia, hipoacusia, tinnitus, vértigo y parálisis facial periférica. Muchas formas de barotrauma son autolimitadas y prevenibles mediante técnicas simples como la deglución de líquidos o maniobras de Valsalva durante las fases de ascenso o descenso. El tratamiento del barotrauma puede ser conservador, médico o quirúrgico, la decisión será individualizada de acuerdo con las características del paciente, gravedad del cuadro y recurrencias. Esto incluye el uso de descongestionantes orales y tópicos, dispositivos de autoinflación, técnicas quirúrgicas, entre otros. La mayoría de estas intervenciones se basan en recomendaciones de expertos y algoritmos extrapolados de guías clínicas para el manejo de otras patologías similares. Esta revisión presenta los principales hallazgos fisiopatológicos y clínicos, las opciones de tratamiento y las medidas preventivas para el barotrauma otorrinolaringológico inducido por el vuelo, en base a la evidencia disponible.

Barotrauma is defined as tissue damage caused by pressure differences between an unventilated space within the body and the surrounding gas or fluid. The most frequent cause of barotrauma is air travel, and a progressive increase in cases over time is expected. The most frequently affected organs are the ear, paranasal sinuses, and facial nerve. The pathophysiology of flight-induced barotrauma is based on exposure to sudden changes in altitude and pressure associated with upper respiratory tract infections and/or Eustachian tube dysfunction. The most frequent symptoms are otalgia, hypoacusis, tinnitus, dizziness, and peripheral facial palsy. Many forms of barotrauma are self-limiting and preventable through simple techniques such as swallowing fluids or performing Valsalva maneuvers during ascent or descent phases. The treatment of barotrauma can be either conservative, medical or surgical, according to patient's characteristics, severity of the condition, and recurrence. This includes the use of oral and topical decongestants, auto-inflation devices, surgical techniques, among others. Most of these interventions are based on expert recommendations and algorithms extrapolated from clinical guidelines for the management of other similar pathologies. This review presents key pathophysiologic and clinical findings, treatment options, and preventive measures for flight-induced otorhinolaryngologic barotrauma, based on available evidence.

Radioquimioterapia neoadyuvante en cáncer de recto: Relevancia clínica del downstaging y la respuesta patológica completa

Antecedentes: La radioquimioterapia neoadyuvante es uno de los pilares del tratamiento del cáncer de recto localmente avanzado. La neoadyuvancia ha demostrado disminuir la recidiva local, generando también un downstaging tumoral, llegando incluso a una respuesta patológica completa (RPC), esta última relacionada con una mejor sobrevida global (SG) y sobrevida libre de enfermedad (SLE). Objetivo: Reportar los resultados anátomo-patológicos del tratamiento con radioquimioterapia en cáncer de recto, analizando su relación con la SG y la SLE. Material y Método: Estudio de cohorte prospectivo. Se analiza base de datos de cirugías coloproctológicas del Hospital Clínico de la Universidad de Chile, entre los años 20042019, incluyendo pacientes con cáncer de recto medio y bajo localmente avanzados, los cuales recibieron neoadyuvancia y posteriormente cirugía. Se realizó el análisis de sobrevida con el método de Kaplan-Meier y el test Log-rank para su comparación. Se consideró estadísticamente significativo un valor de p < 0,05. Resultados: 411 pacientes fueron operados por cáncer de recto, 143 pacientes recibieron neoadyuvancia, el 19% registró RPC. La SG del grupo con RPC fue 94% (IC 95%; 59,79-79,41%) mientras que la del grupo sin RPC fue 71% (IC 95%; 66,64-99,20%) (p = 0,018), la SLE en aquellos pacientes con RPC alcanzó un 100%, mientras que en aquellos sin RPC fue 74% (IC 95%; 64,08-81,28) (p = 0,008). Conclusiones: Los pacientes con RPC mostraron mejores resultados a largo plazo que aquellos sin RPC. La RPC podría indicar un perfil tumoral biológico favorable, con menos tendencia a la recurrencia y mejor supervivencia.

Background: One of the mainstays in the treatment of locally advanced rectal cancer is neoadjuvant chemoradiotherapy. Neoadjuvant therapy have demonstrated to decrease local recurrence, also generating tumor downstaging, even leading to a pathological complete response (PCR), the latter related to better overall survival (OS) and disease-free survival (SLE). Aim: To report the anatomo-pathological results of treatment with chemoradiotherapy in rectal cancer, analyzing the relationship with OS and SLE. Material and Method: Prospective cohort study. A database of colorectal surgeries from the Clinical Hospital of the University of Chile between the years 2004-2019, including patients with locally advanced low and middle rectal cancer, who received neoadjuvant and later surgery. Survival analysis was made with the Kaplan-Meier method and the Log-rank test for comparison. A value of p < 0.05 was considered statistically significant. Results: 411 patients underwent surgery for rectal cancer, 143 patients received neoadjuvant therapy, 19% registered PCR. The OS of the group with PCR was 94% (95% CI; 59.79-79.41%) while that of the group without PCR was 71% (95% CI; 66.64-99.20%) (p = 0.018), the SLE in those patients with PCR reached 100%, while in those without PCR it was 74% (95% CI; 64.08-81.28) (p = 0.008). Conclusions: Patients with PCR have better long-term results than those without PCR. PCR could indicate a favorable biological tumor profile, with less tendency to recurrence and improved survival.

Biomateriales y tecnologías de impresión 3D en entrenamiento quirúrgico en otorrinolaringología: una revisión / Biomaterials and technologies of 3D printing in surgical training on otorhinolaryngology: a revision

La tecnología de fabricación aditiva o impresión 3D se ha posicionado como una herramienta transversal y de uso creciente en el mundo productivo y científico que ha otorgado la posibilidad de diseñar y crear elementos y modelos de diversa complejidad. En el área biomédica ha presentado un aumento significativo de sus aplicaciones a través del tiempo, actualmente teniendo relevancia en ámbitos como el planeamiento quirúrgico, la creación de prótesis, modelos anatómicos para educación y entrenamiento quirúrgico. Actualmente existen diversas dificultades que limitan la formación quirúrgica, especialmente en ciertas áreas de la otorrinolaringología como la cirugía de oído. El objetivo de la presente revisión narrativa fue actualizar los usos de la tecnología de impresión 3D para la creación de modelos para entrenamiento quirúrgico en otorrinolaringología, destacando sus potenciales usos en otología, rinología, cirugía de base de cráneo y vía aérea.

Additive manufacturing technology or 3D printing has positioned itself as a cross-cutting tool of increasing use in the productive and scientific world that has given the possibility of designing and creating different elements and models of varying complexity. In the biomedical area, it has presented a significant increase in its applications over time, currently having relevance in areas such as surgical planning, the creation of prostheses, anatomical models for education and surgical training. Currently there are various difficulties that limit surgical training, especially in certain areas of otorhinolaryngology such as ear surgery. The objective of this narrative review was to update the uses of 3D printing technology for the creation of models for surgical training in otorhinolaryngology, highlighting its potential uses in otology, rhinology, skull base and airway surgery.

The ICTUS Study: A Prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort.

The long-term objective of the ICTUS study is to identify milestones in Alzheimer's disease (AD) progression and to develop a model to predict disease course in individual AD patients in Europe. The secondary objectives are to describe the patterns of prescribing, and the socioeconomic impact of AD in Europe. Between 2003 and 2005 1,380 patients with probable AD were recruited in specialised (secondary care) clinics in 12 European countries. Their mean age was 76 years and they had a mean of 8.0 +/- (SD) 4.6 years of education. Thirty-five percent were male. The mean MMSE score was 20.4 +/- (SD) 4.0. Forty-three percent had very mild dementia (CDR 0.5) and 44% had mild dementia (CDR 1). All patients completed baseline evaluation and biannual follow-up is ongoing. The goals of the current study are to describe the specific methods for recruitment in this crosscultural setting and the characteristics of the inception ICTUS cohort, including clinical features, co-morbidity, neuropsychological performance, neuropsychiatric symptoms, functional impairment and social burden.

Unique DNA repair properties of a xeroderma pigmentosum revertant.

A group A xeroderma pigmentosum revertant with normal sensitivity was created by chemical mutagenesis. It repaired (6-4) photoproducts normally but not pyrimidine dimers and had near normal levels of repair replication, sister chromatid exchange, and mutagenesis from UV light. The rate of UV-induced mutation in a shuttle vector, however, was as high as the rate in the parental xeroderma pigmentosum cell line.

Six and 18-month changes in mild to moderate Alzheimer's patients treated with acetylcholinesterase inhibitors: what can we learn for clinical outcomes of therapeutic trials?

BACKGROUND: Clinical trials in Alzheimer's disease (AD) include patients benefiting from recent improvements in AD management. OBJECTIVE: To observe the progression of Alzheimer's disease (AD) after 6 and 18 months in patients treated with acetylcholinesterase inhibitors (AChEI) in order to determine the best duration of follow-up necessary to demonstrate the impact of new drugs. METHODS: Six hundred and eleven patients included in the REAL.FR cohort were treated with AChEI at baseline. We describe the cognitive, functional, behavioural, nutritional and global changes in the 509 and 364 patients who completed 6 and 18 months of follow-up, respectively, and who did not discontinue treatment. RESULTS: After 6 and 18 months, we observed a statistically significant change in the MMSE (-0.54 +/- 3.13 at 6 months and -2.90 +/- 4.10 at 18 months), ADAS-cog (1.58 +/- 5.23 and 4.02 +/- 6.83), ADL (-0.30 +/- 0.79 and -0.84 +/- 1.20), IADL (-0.31 +/- 0.95 and -0.94 +/- 1.20), CDR sum of boxes (0.75 +/- 2.03 and 2.65 +/- 3.18) and MNA scores (-0.42 +/- 2.89 and -0.95 +/- 3.57), demonstrating the progression of AD. But on examining these changes, it appears that even if they were statistically significant at 6 months, they do not appear to be clinically relevant or sufficient to allow the observation of the effect of a new drug at this time, whereas such observation would be possible after 18 months. Similar results were obtained in a subgroup of patients who answer to the inclusion criteria of disease modifying trials which confirms the need for having 18 months of follow-up. CONCLUSION: Changes in AD in patients under AChEI treatment are not sufficient to demonstrate the effect of a new treatment at 6 months. However, 18-month trials appear to have the potential to demonstrate clearly the effect of a new drug.