Editorial for special issue on advances in Actuarial Science and quantitative finance.

This article provides an overview of all papers published on the special issue, Advances in Actuarial Science and Quantitative Finance. The special issue is intended to collect articles that reflect the latest development and emerging topics in these closely related two areas. Topics included in this special issue range from actuarial and risk theory, to optimal control for finance and insurance, to statistical inferences of financial and insurance models, to pricing, valuation and reserving.

Photonic lantern tip/tilt detector for adaptive optics systems.

In this work, we demonstrate a four-core multicore fiber photonic lantern tip/tilt wavefront sensor. To diagnose the low-order Zernike aberrations, we exploit the ability of the photonic lantern to encode the characteristics of a complex incoming beam at the multimode facet of the sensor to intensity distributions at the multicore fiber output. Here, we provide a comprehensive numerical analysis capable of predicting the performance of fabricated devices and experimentally demonstrate the concept. Two receiver architectures are implemented to discern tip/tilt information by (i) imaging the four-core fiber facet on a 2D detector and (ii) direct power measurement of the single mode outputs using a multicore fiber multiplexer and photodetectors. For both receiver schemes, an angular detection window of ∼0.4∘ at 1064 nm can be achieved. Our results are expected to further facilitate the development of intensity-based fiber wavefront sensors for adaptive optics systems.

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aß in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

Effect of dental restorative materials surface roughness on the in vitro biofilm formation of Streptococcus mutans biofilm.

PURPOSE: To evaluate Streptococcus mutans biofilm formation over different restorative dental materials. METHODS: Using a bioreactor over 72 hours, four commercially available ceramics were evaluated: IPS E-max Press, IPS E-max CAD, Lava Ultimate CAD-CAM, Vita Enamic and two resin composites (SR Nexco Paste and Brilliant NG). The results were evaluated using atomic force microscopy and confocal microscopy, the biofilm was stained and the arbitrary fluorescence units (AFU) quantified. RESULTS: The results showed that IPS E-max CAD had the lowest roughness values (4.29±1.79 nm), while the highest values were observed for Vita Enamic discs ( (77.13±17.35 nm). Analysis of S. mutans biofilm formation by AFU revealed lower values for IPS E-max CAD (6.77±1.67 nm); the highest values were found for Lava Ultimate (79.99±22.23 nm). Regarding the composite groups, SR Nexco Paste showed roughness values of 15.07±2.77 nm and lower arbitrary fluorescence units of 30.92±12.01 nm than Brilliant NT. There was a correlation between the surface roughness of ceramics and composite with S. mutans biofilm formation. CLINICAL SIGNIFICANCE: The adhesion of oral bacteria to restorative dental materials plays a key role in the success of dental treatment; the surface roughness influences the S. mutans biofilm formation.

Predisposing factors for acute kidney injury in Hispanic patients treated with diuretics for decompensated heart failure.

OBJECTIVE: In patients with congestive heart failure (CHF), use of loop diuretic therapy may result in acute kidney insufficiency (AKI). We assessed the factors that contributed to the development of AKI in patients with CHF treated with loop diuretics in a sample of patients who attended the Cardiovascular Center of Puerto Rico and the Caribbean (CCPRC). METHODS: Medical records of 236 patients admitted between: January 1, 2008 to December 31, 2008 with the diagnosis of CHF were reviewed. Diagnosis of CHF based on symptoms and signs was confirmed by echocardiography. Twenty six (26) patients with significant valvular disease and four (4) patients who did not receive diuretics during hospitalization were excluded. Hospital course was observed until diuretic therapy was discontinued or patient was discharged. AKI was defined as a 25% increase in serum creatinine level after the start of diuretic therapy. The study sample was categorized in two groups: patients who developed AKI and those who did not. Variables associated with AKI (p<0.05) in the bivariate logistic regression models were included in the multivariate logistic regression models. RESULTS: In the multivariate logistic regression model, only a greater dose of diuretic therapy (>80 mg/dl) and history of diabetes mellitus were significantly (p<0.05) associated with AKI. CONCLUSION: Analysis of data shows that increased doses of diuretic therapy and history of diabetes mellitus were significantly associated with AKI in patients with CHF. This study highlights the importance of monitoring the doses of diuretic therapy during hospitalization, in this group of patients.

Surface degradation and biofilm formation on hybrid and nanohybrid composites after immersion in different liquids.

PURPOSE: This study evaluated the association of surface degradation and formation of Streptococcus mutans (S. mutans) biofilm in resin-based composites (RBCs) after storage in different acidic liquids. METHODS: To evaluate microhardness and surface micromorphology, hybrid and nanohybrid RBC discs were stored in artificial gastric acid, cola drink, orange juice, artificial saliva, and distilled water for three intervals of 15 min per day for 7, 15, and 30 days. After 30 days of storage, surface roughness was analyzed, and the RBC discs were placed in a biofilm reactor inoculated with S. mutans to evaluate surface biofilm formation. RESULTS: As compared with nanohybrid RBCs, roughness and surface microhardness values were significantly lower (P < 0.05) for hybrid RBCs stored in artificial gastric acid, followed by specimens stored in cola drink and orange juice. Artificial gastric acid caused greater surface degradation, which increased the biomass of S. mutans on the surface of both RBC types. CONCLUSION: Surface degradation of hybrid and nanohybrid RBCs correlated with the pH of the liquid, while S. mutans biofilm formation was associated with increased surface roughness in hybrid RBCs.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

Empowerment in older psychiatric inpatients: development of the empowerment questionnaire for inpatients (EQuIP).

OBJECTIVE: To develop a questionnaire that measures levels of empowerment experienced by older adults admitted to a psychiatric ward. DESIGN: Diverse views were sought to inform the questionnaire through a triangulation method; opinions of researchers were collected through a Delphi survey, clinical staff from different disciplines completed questionnaires, and patients participated in two focus group sessions. Once the questionnaire was developed, the authors asked patients to complete it alongside other instruments. SETTINGS: Eight psychiatric wards of seven hospitals in and around London for people aged more than 65 years with a range of organic and functional mental health problems. PARTICIPANTS: Eighty-seven patients with a functional psychiatric diagnosis participated in the psychometric evaluation of the instrument; 28 completed the scale twice for test-retest reliability. MEASURES: Measures of quality of life (World Health Organisation Quality of Life - Abbreviated Version), degree of dependency (Care Dependency Scale), satisfaction with care (Psychiatric Care Satisfaction Questionnaire [PCSQ]), and psychosocial functioning (GAF) were used to evaluate psychometric properties of the empowerment questionnaire for inpatients (EQuIP). RESULTS: The EQuIP is a measure of empowerment, which computes the subjective importance of the different aspects of psychiatric care for the individual patient. It had high internal consistency (Cronbach's alpha = 0.88) and reasonable concurrent validity (correlation with PCSQ as a measure of satisfaction with care, r(85) = 0.65, p = 0.01). High test-retest variability may signify fluidity of the construct of empowerment. CONCLUSION: The EQuIP may be used to assess empowerment in older psychiatric inpatients.

Observation of twist-induced geometric phases and inhibition of optical tunneling via Aharonov-Bohm effects.

Geometric phases appear ubiquitously in many and diverse areas of the physical sciences, ranging from classical and molecular dynamics to quantum mechanics and solid-state physics. In the realm of optics, similar phenomena are known to emerge in the form of a Pancharatnam-Berry phase whenever the polarization state traces a closed contour on the Poincaré sphere. While this class of geometric phases has been extensively investigated in both free-space and guided wave systems, the observation of similar effects in photon tunneling arrangements has so far remained largely unexplored. Here, we experimentally demonstrate that the tunneling or coupling process in a twisted multicore fiber system can display a chiral geometric phase accumulation, analogous to the Aharonov-Bohm effect. In our experiments, the tunneling geometric phase is manifested through the interference of the corresponding supermodes. Our work provides the first observation of Aharonov-Bohm suppression of tunneling in an optical setting.

Outcomes after heart valve replacement surgery at the Cardiovascular Center of Puerto Rico and the Caribbean.

BACKGROUND: Heart valve surgery is the second most common type of cardiac surgery. However, there is limited information about the outcomes associated to these types of surgeries. METHODS: A retrospective review was performed in 91 Puerto Rican patients who underwent elective heart valve replacement surgery at the Cardiovascular Center of Puerto Rico and the Caribbean (CCPRC) between January 2004 and January 2005. Demographic features, comorbidities, electrocardiographic findings, surgical data, length of hospitalization, and associated in-hospital complications were determined. Data were examined using Fisher's exact test, chi-square test, analysis of variance and student t test to analyze differences between the study groups. RESULTS: The mean age of the study population was 61.1 +/- 13.2 years; 48 patients (52.7%) were males. Sixty-one patients (67.0%) had aortic valve replacement whereas thirty patients (33.0%) had mitral valve replacement. Patients with aortic valve replacement were older (63.1 +/- 13.5 years vs. 56.0 +/- 11.2 years, p < 0.05) and more likely to present left ventricular hypertrophy (57.4% vs. 16.7%, p < 0.05) than patients with mitral valve replacement. On the other hand, patients with mitral valve replacement presented more frequently atrial fibrillation (43.3% vs. 9.8%, p < 0.05) than those with aortic valve replacement. The estimated in-hospital mortality rate was 1.1%. CONCLUSIONS: A review of heart valve replacement surgery conducted between January 2004 and January 2005 at the CCPRC revealed that the in-hospital mortality rates, complications, surgical times, and length of hospitalization at the CCPRC compares favorably with those reported in the literature.

Dose- and administration time-dependent effects of nifedipine gits on ambulatory blood pressure in hypertensive subjects.

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow-release, once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest-activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1+/-10.7 yrs of age, with grade 1-2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up-titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non-responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose-dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.

Uncorrected tetralogy of Fallot with agenesis of the left pulmonary artery in a 70-year-old elderly female.

Tetralogy of Fallot is the most common cyanotic congenital heart disease in children. It is usually detected in early infancy due to symptoms related to cyanosis and right to left shunting of blood through a large ventricular septal defect. Uncorrected it is associated to a very poor prognosis, with only 3% of adults surviving by age 40 years of age. The combination of tetralogy of Fallot with agenesis of the pulmonary arteries is a rare congenital condition with some reports describing it in 2-3% of patients with Tetralogy of Fallot (ToF). Some rare reports of prolonged survival in patients with uncorrected ToF have been described in the medical literature with some patients living until late adulthood. Here we describe the rare presentation of an elderly female with uncorrected ToF and agenesis of the left pulmonary artery.

Bland-White Garland syndrome with Takeuchi repair: case report and review of literature.

Anomalous origin of the left coronary artery from the pulmonary artery (Bland-White Garland Syndrome) is extremely rare. With surgical reestablishment of two-coronary system on diagnosis yields excellent results with progressive nearly total myocardial recovery. A 30-year-old woman was admitted to hospital due to shortness of breath, ortopnea and increased abdominal girth nineteen years after Takeuchi repair of anomalous origin of left coronary artery from the pulmonary trunk. At initial evaluation we found worsening of preexistent mitral regurgitation requiring mitral valve replacement after exclude ongoing or recurrent myocardial insult. This work reviews the pathophysiology and natural history of anomalous origin of the left coronary artery from the pulmonary artery after Takeuchi repair.

Constrictive pericarditis.

Constrictive pericarditis is a rare but severely disabling consequence of the chronic inflammation of the pericardium, leading to an impaired filling of the ventricles and reduced ventricular function. Patients complain about fatigue, peripheral edema, breathlessness and abdominal swelling; signs and symptoms of right-sided heart failure. Besides history and physical examination, diagnostic studies aid in the diagnosis, including electrocardiogram, chest x-ray, echocardiogram, chest CT and/or MRI, and hemodynamic measurements. Medical management with diuretics and salt restriction is useful for symptomatic relief of fluid overload and peripheral edema, but patients ultimately become refractory. Although conservative treatment may alleviate the patient's symptoms, pericardiectomy remains the onlydefinitive treatment for the disease. An interesting and representative case of constrictive pericarditis is presented in this article.

[Effects of time-dependent administration of antihypertensive treatment in patients with resistant hypertension]. / Efectos de la administración temporalizada de fármacos antihipertensivos en pacientes con hipertensión arterial resistente.

BACKGROUND AND OBJECTIVE: Patients with resistant hypertension represent an important clinical problem due to their poor control, high prevalence of target organ damage, and the associated increase in cardiovascular risk. Therapeutic strategies in resistant hypertension currently include a sequential change of drugs or the synergic combination of new drugs. Most patients, however, receive all their drugs in a single morning dose. We have evaluated the impact on the circadian pattern of blood pressure (BP) of modifying the time of treatment without increasing the number of prescribed drugs. PATIENTS AND METHOD: We studied 123 patients with resistant hypertension (73 men and 50 women), 59.9 (11.9) years of age, who were receiving 3 antihypertensive drugs in a single morning dose. Patients were randomly assigned to one of two groups according to the modification in their treatment strategy: a) Changing one of the drugs, but keeping all 3 in the morning. b) The same approach but prescribing one of the drugs to be taken at bedtime. Blood pressure was measured at 20-minute intervals from 07:00 to 23:00 hours and at 30-minute intervals at night for 48 consecutive hours at baseline and after 3 months of treatment with the new therapeutic scheme. RESULTS: There was a small and non-significant BP reduction when all drugs were still taken on awakening (p > 0.374). On baseline, only 22% of the patients in this group were dippers, and this percentage was further reduced to 15% after 3 months of therapy with all drugs on awakening. The blood pressure reduction was statistically significant (8.6 and 5.9 mmHg for systolic and diastolic blood pressure; p < 0.001) with one drug at bedtime. This effect was markedly larger in the nocturnal mean of blood pressure. Thus, while only 13% of the patients in this group were dippers at baseline, 53% were already dippers after 3 months of therapy. CONCLUSIONS: Results from this prospective trial indicate that, in patients with resistant hypertension, time of treatment may be more important for patient control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination.

[Chronotherapy with torasemide in hypertensive patients: increased efficacy and therapeutic coverage with bedtime administration]. / Cronoterapia con torasemida en pacientes hipertensos: aumento de la duración y la eficacia terapéuticas con su administración a la hora de acostarse.

BACKGROUND AND OBJECTIVE: Torasemide is a high ceiling loop diuretic frequently used for treatment of heart failure, renal failure and hypertension, according to results mainly based on clinic blood pressure measurements, without proper evaluation of the 24-hour efficacy of the drug. Accordingly, we investigated the time-dependent antihypertensive efficacy of torasemide in hypertensive patients. PATIENTS AND METHOD: We studied 58 patients with grade 1-2 essential hypertension (25 men and 33 women), 48.7 (11.9) years of age, randomly assigned to receive torasemide (5 mg/day) either upon awakening or at bedtime. Blood pressure was measured by ambulatory monitoring for 48 consecutive hours before and after 6 weeks of therapy. RESULTS: Efficacy of torasemide was significantly higher with bedtime dosing (11.2 and 8.0 mmHg reduction in the 24-hour mean of systolic and diastolic blood pressure, respectively) as compared to the administration of the drug on awakening (6.2 and 3.7 mmHg reduction in systolic and diastolic blood pressure). The percentage of patients with controlled ambulatory blood pressure after treatment was also higher after bedtime treatment (54% versus 27%). The time-response curves indicate a full 24-hour therapeutic duration only when torasemide was administered before bedtime. With regard to the safety profile, 2 patients presented secondary effects (abdominal pain, diarrhea) in morning dose, and 4 patients taking the drug at bedtime reported nicturia. CONCLUSIONS: A dose of 5 mg/day torasemide is effective for blood pressure reduction after bedtime administration. The differences in efficacy and therapeutic duration as a function of the circadian time of treatment with torasemide here documented should be taken into account when prescribing this loop diuretic for treatment of patients with essential hypertension.

Uneventful pregnancy and delivery in a patient with idiopathic pulmonary hypertension: a case report.

Idiopathic pulmonary hypertension is a rare disease characterized by sustained elevation of the pulmonary artery pressure and pulmonary vascular resistance, normal pulmonary artery wedge pressure, in the absence of a known cause. Prior reports suggest a very high maternal mortality in patients with idiopathic pulmonary hypertension undergoing pregnancy, and for that the recommendation has been avoidance of pregnancy (or termination if the patient is already pregnant). On the other hand, there have been multiple reports of patients with idiopathic pulmonary hypertension sustaining pregnancy and labor without major complications. This case report illustrates the course of pregnancy and labor in a patient diagnosed with idiopathic pulmonary hypertension. At age 24, the patient started with symptoms of shortness of breath and chest pain, and upon evaluation she was found with moderately severe idiopathic pulmonary hypertension. One year and 8 months later the patient becomes pregnant, and begins follow up with gynecology and cardiology. During this time the patient was asymptomatic, and did not have any clinical evidence of pulmonary hypertension. The risks of pregnancy were discussed with the patient, and she decided to continue pregnancy. She had an uneventful pregnancy, complicated only by preterm labor at 34 weeks and 5 days of gestation. She had spontaneous labor and delivered vaginally a healthy baby boy, weighting 4 pounds and 12 ounces. No invasive monitoring was used. The mother and the baby were discharged home 48 hours postpartum. Seven months later the patient returned for evaluation, presenting evidence of severe pulmonary hypertension. She has been followed up ever since by a cardiologist and currently is stable but symptomatic. This report adds to the amount of evidence that suggests that pregnancy and labor in a patient with idiopathic pulmonary hypertension may have a better outcome than previously reported. The decision of undertaking and/or continuing pregnancy in a patient with idiopathic pulmonary hypertension relies ultimately on the patient's choice, but should be done on an individual basis after careful evaluation of the risks. Finally, the need of close follow up with a multidisciplinary team is mandatory in the patient with idiopathic pulmonary hypertension that wishes to undergo pregnancy.

Seasonal variation of fibrinogen in dipper and nondipper hypertensive patients.

BACKGROUND: A seasonal variation with higher values in winter has been previously reported in plasma fibrinogen, a recognized marker of the potential risk of myocardial infarction and stroke. The lack of nocturnal decline in blood pressure has also been associated with an increase in cardiovascular events. Accordingly, we have compared the yearly variation of plasma fibrinogen in dipper and nondipper hypertensive patients. METHODS AND RESULTS: We studied 1006 stage 1 to 2 hypertensive patients (482 men and 524 women, 53.0+/-13.4 years of age). Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours. Physical activity was simultaneously evaluated at 1-minute intervals with a wrist actigraph. A blood sample was collected on the same day before starting blood pressure monitoring. The circannual variation of fibrinogen was established for all patients as well as for subgroups of dippers and nondippers (n=513; nocturnal blood pressure decline <10%) by multiple-component analysis. For the whole group of patients, fibrinogen was characterized by a highly significant seasonal variation (P<0.001) with a mean value of 318 mg/dL, double circannual amplitude (extent of predictable change along the year) of 40 mg/dL, and time of peak value in February. Throughout the year, the nondippers showed higher plasma fibrinogen levels than did the dippers (P<0.001). CONCLUSIONS: The elevated plasma fibrinogen levels in nondipper patients appear to be directly related to their increased risk in vascular events, which are more prominent during the late winter months.

Evaluation of the extent and duration of the "ABPM effect" in hypertensive patients.

OBJECTIVES: The goal of this study was to test and quantify the extent and duration over time of a possible pressor effect due to ambulatory monitoring. BACKGROUND: The use of ambulatory blood pressure monitoring has provided a method of blood pressure (BP) assessment that compensates for some of the limitations of office values. While a "white-coat" pressor effect on conventional measurements has been defined and frequently used for the improved evaluation of hypertensive patients, there has not been clear indication that the ambulatory technique could also influence BP. METHODS: We studied 538 mild-to-moderate hypertensive patients (233 men), 54.2 +/- 14.2 (mean +/- SD) years of age. Blood pressure and heart rate were measured at 20-min intervals during the day and at 30-min intervals at night for 48 consecutive hours, and physical activity was simultaneously evaluated at 1-min intervals with a wrist actigraph. One-third of the patients were evaluated twice or more times. RESULTS: In both treated and untreated hypertensive patients evaluated for the first time, results indicate a statistically significant (p < 0.001) reduction during the second day of monitoring as compared with the first in the diurnal mean of systolic and diastolic BP, but not in heart rate or physical activity. This pressor effect remains statistically significant for the first 6 h to 8 h of monitoring independently of gender, days of the week of monitoring or number of antihypertensive drugs used by the treated patients. The nocturnal mean of BP was, however, similar between both days of sampling. This "ambulatory monitoring effect" was not observed when the patients were evaluated after the same sampling scheme for the second or successive times three months apart. CONCLUSIONS: Ambulatory monitoring for 48 consecutive hours reveals a statistically significant pressor response that could reflect a novelty effect in the use of the monitoring device for the first time. This effect has marked implications in both research and clinical daily practice for a proper diagnosis of hypertension and evaluation of treatment efficacy by the use of ambulatory monitoring.

Treatment of non-dipper hypertension with bedtime administration of valsartan.

BACKGROUND: Previous results have indicated that valsartan administration at bedtime, as opposed to upon wakening, may improve the diurnal: nocturnal ratio of blood pressure without loss in 24-h coverage and efficacy. OBJECTIVES: To investigate the administration time-dependent antihypertensive efficacy of valsartan in non-dipper patients. METHODS: We studied 148 non-dipper patients with grade 1-2 essential hypertension, aged 53.0+/-12.6 years, who were randomly assigned to receive valsartan (160 mg/day) as a monotherapy either on awakening or at bedtime. Blood pressure was measured every 20 min during the day and every 30 min at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per subject basis. RESULTS: The significant blood pressure reduction after 3 months of valsartan (P<0.001) was similar for both treatment times (13.1 and 8.5 mmHg reduction in the 24-h mean of systolic and diastolic blood pressure with morning administration; 14.7 and 10.3 mmHg with bedtime administration; P>0.126 for treatment-time effect). The diurnal: nocturnal ratio of blood pressure was significantly increased only when valsartan was administered before bedtime, which resulted in 75% of the patients in this group reverting to dippers, a significant increase in the percentage of patients with controlled blood pressure over 24 h, and a reduction in urinary albumin excretion. CONCLUSIONS: In non-dipper hypertensive patients, dosing time with valsartan should be chosen at bedtime, for improved efficacy during the nocturnal resting hours, as well as the potential associated reduction in cardiovascular risk.