Effect of periconceptional nutrition on the growth, behaviour and survival of the neonatal lamb.

Periconceptional nutrition (PCN) can influence foetal hypothalamo-pituitary adrenal (HPA) axis function and alter cortisol secretion with possible consequences for maturation and growth of major organs, gestation length and behaviour. We examined effects of PCN on phenotype and survival of the neonatal lamb in 466 Merino ewes allocated to treatments providing 70%, 100% and 150% respectively, of maintenance requirements for 17 days prior and 6 days after insemination. Gestation length and birth weight for lambs in PCN treatment groups was similar (P > 0.05) but low PCN decreased the size of the neonate (crown-rump-length and metacarpal length P < 0.05). A subset of lambs euthanased at 5 days of age further showed that low PCN decreased the amount of peri-renal fat (P < 0.05) and increased liver mass (P < 0.05) while high PCN increased neck thymus and ovary mass (P < 0.05). Neonatal lambs from low PCN ewes returned faster to their mothers after release (P < 0.05) and contacted the udder in the shortest time (P < 0.05). Significant interactions between PCN treatment and sex (P < 0.05) and between PCN treatment and ewe age (P < 0.05) were also observed for time lambs took to follow the ewe. Survival of lambs was similar but potential differences may have been masked by favourable weather conditions. In conclusion, this study provides evidence of significant changes in lamb growth and development dependent on PCN and, for the first time, links these changes with significant changes in behaviour of the neonate. The impact of these effects on lamb survival and potential reproductive capacity of female offspring remains to be determined.

Predicting the risk of Clostridium difficile infection following an outpatient visit: development and external validation of a pragmatic, prognostic risk score.

Increasing morbidity related to Clostridium difficile infection (CDI) has heightened interest in the identification of patients who would most benefit from recognition of risk and intervention. We sought to develop and validate a prognostic risk score to predict CDI risk for individual patients following an outpatient healthcare visit. We assembled a cohort of Kaiser Permanente Northwest (KPNW) patients with an index outpatient visit between 2005 and 2008, and identified CDI in the year following that visit. Applying Cox regression, we synthesized a priori predictors into a CDI risk score, which we validated among a Kaiser Permanente Colorado (KPCO) cohort. We calculated and plotted the observed 1-year CDI risk for each decile of predicted risk for both cohorts. Among 356 920 KPNW patients, 608 experienced CDI, giving a 1-year incidence of 2.2 CDIs per 1000 patients. The Cox model differentiated between patients who do and do not develop CDI: there was a C-statistic of 0.83 for KPNW. The simpler points-based risk score, derived from the Cox model, was validated successfully among 296 550 KPCO patients, with no decline in the area under the receiver operating characteristic curve: 0.785 (KPNW) vs. 0.790 (KPCO). The predicted risk for CDI agreed closely with the observed risk. Our CDI risk score utilized data collected during usual care to successfully identify patients who developed CDI, discriminating them from patients at the lowest risk for CDI. Our prognostic CDI risk score provides a decision-making tool for clinicians in the outpatient setting.

Observation of entanglement-dependent two-particle holonomic phase.

Holonomic phases--geometric and topological--have long been an intriguing aspect of physics. They are ubiquitous, ranging from observations in particle physics to applications in fault tolerant quantum computing. However, their exploration in particles sharing genuine quantum correlations lacks in observations. Here, we experimentally demonstrate the holonomic phase of two entangled photons evolving locally, which, nevertheless, gives rise to an entanglement-dependent phase. We observe its transition from geometric to topological as the entanglement between the particles is tuned from zero to maximal, and find this phase to behave more resiliently to evolution changes with increasing entanglement. Furthermore, we theoretically show that holonomic phases can directly quantify the amount of quantum correlations between the two particles. Our results open up a new avenue for observations of holonomic phenomena in multiparticle entangled quantum systems.

Adding nebivolol to ongoing antihypertensive therapy improves blood pressure and response rates in patients with uncontrolled stage I-II hypertension.

This study assessed blood pressure (BP) reductions and response rates following addition of nebivolol to ongoing antihypertensive therapy in patients with uncontrolled stage I-II hypertension despite antihypertensive treatment. Patients with an average sitting diastolic BP (SiDBP) > or =90 and < or =109 mm Hg while taking an antihypertensive regimen were included in this double-blind, placebo-controlled, parallel-group study. The primary efficacy end point was reduction from baseline to week 12 in mean trough SiDBP. In total, 669 patients were randomized to once-daily nebivolol 5, 10 or 20 mg or placebo. Addition of nebivolol 5, 10 and 20 mg significantly reduced BP; placebo-subtracted least squares mean reductions in trough SiDBP were -3.3, -3.5 and -4.6 mm Hg, respectively (P<0.001) and -5.7, -3.7 and -6.2 mm Hg in trough sitting systolic BP (SiSBP), respectively (P< or =0.015). Adding nebivolol 5-20 mg resulted in significantly more responders (SiDBP <90 or > or =10 mm Hg reduction; range: 53.0-65.1 vs 41.3% with placebo; P< or =0.028) and significantly better control rates (SiSBP/SiDBP <140/90 mm Hg; range: 41.3-52.7 vs 29.3% with placebo; P< or =0.029). Nebivolol was well tolerated; the incidence of adverse events with nebivolol was similar to that with placebo (40.2 vs 38.9%, respectively; P=0.763). Addition of once-daily nebivolol to ongoing antihypertensive therapy provided significant additional BP reductions and better response rates in patients with uncontrolled hypertension and was well tolerated.

Secular trends in kidney disease: is the decreased incidence of renal replacement therapy due to a decrease in chronic kidney disease incidence?

AIMS: Little is known about trends in renal replacement therapy among patients with chronic kidney disease (CKD) or about changes in the incidence of CKD. We studied the incidence of renal replacement therapy within the population of a health maintenance organization (HMO) both among the entire HMO population and among those with CKD. METHODS: We calculated yearly incidence rates of renal replacement therapy for each year from 1998 to 2005. We defined CKD using the National Kidney Foundation definition of 2 estimated glomerular filtration rates below 60 ml/min/1.73 m2 90 or more days apart. Poisson regression assessed year-to-year differences. RESULTS: The number of patients with CKD rose consistently from 3,861 in 1998 to 5,242 in 2005. The proportion of patients who had been diagnosed with hypertension rose from 86.7% (starting renal replacement therapy) or 34.5% (with CKD) to 99.1 and 46.9%. The proportion of patients with diabetes changed little throughout the years studied. The mean estimated glomerular filtration rate among CKD patients rose minimally from 38.4 ml/min/1.73 m2 in 1998 to 39.9 ml/min/1.73 m2 in 2005. Age- and sex-adjusted rates of RRT among patients with CKD varied (p=0.0034), but did not follow a consistent pattern over time. CONCLUSIONS: Incidence of renal replacement therapy among patients with CKD changed little between 1998 and 2005, despite an increase in the number of patients diagnosed with CKD. The discrepancy may be due to increased laboratory identification of CKD.

Harnessing stakeholder perspectives to improve the care of osteoporosis after a fracture.

UNLABELLED: This study used in-depth interviews and focus groups to evaluate osteoporosis care after a fracture. Patients (eligible women aged 67 who sustained a clinical fracture(s)), clinicians, and staff stated that an outreach program facilitated osteoporosis care management, but more-tailored education and support and increased participation of orthopedic specialists appear necessary. INTRODUCTION: Osteoporosis treatment reduces fracture risk, but screening and treatment are underutilized, even after a fracture has occurred. This study evaluated key stakeholder perspectives about the care of osteoporosis after a fracture. METHODS: Participants were from a nonprofit health maintenance organization in the United States: eligible women members aged 67 or older who sustained a clinical fracture(s) (n = 10), quality and other health care managers (n = 20), primary care providers (n = 9), and orthopedic clinicians and staff (n = 28); total n = 67. In-depth interviews and focus groups elicited participant perspectives on an outreach program to patients and clinicians and other facilitators and barriers to care. Interviews and focus group sessions were transcribed and content-analyzed. RESULTS: Patients, clinicians, and staff stated that outreach facilitated osteoporosis care management, but important patient barriers remained. Patient knowledge gaps and fatalism were common. Providers stated that management needed to begin earlier, and longer-term patient support was necessary to address adherence. Orthopedic clinicians and staff expressed lack of confidence in their osteoporosis management but willingness to encourage treatment. CONCLUSIONS: Although an outreach program assisted with the management of osteoporosis after a fracture, more-tailored education and support and increased participation of orthopedic specialists appear necessary to maximize osteoporosis management.

HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications.

Uterine papillary serous carcinoma (UPSC) is a highly aggressive variant of endometrial cancer with features similar to high-grade ovarian cancer. Patients tend to be elderly, thin, have a high grade tumor with extensive extrauterine disease at the time of diagnosis. The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistochemistry in <25% of ovarian cancers and 20-30% of breast cancers, and <10% of endometrial cancer. There are prognostic and therapeutic implications associated with the overexpression of this transmembrane protein. Herceptin, a humanized murine monoclonal antibody directed against the extracellular domain of the HER-2/neu protein, is being used to treat breast cancer that overexpresses HER-2/neu. We reviewed all patients diagnosed with UPSC between 1999-2001. Twenty-six patients were identified, and 19 patients had specimens available for evaluation. We performed immunohistochemical analysis (Herceptest, Dako, Carpinteria, CA) on 19 paraffin embedded blocks of UPSC tumors looking for HER-2/neu over expression. Five out of 19 (26%) stained heavily (3+) for HER-2/neu receptor protein. Four of these five patients had advanced disease at diagnosis. Two of these patients were subsequently treated with Herceptin; one with complete response and one with stable disease based on CT scan and CA-125 findings. Targeting HER-2/neu may be beneficial for a select group of patients with UPSC. We are continuing to evaluate samples for HER-2/neu over expression by fluorescence in situ hybridization (FISH).

The cost-effectiveness of screening for oral cancer in primary care.

OBJECTIVES: To use a decision-analytic model to determine the incremental costs and outcomes of alternative oral cancer screening programmes conducted in a primary care environment. DESIGN: The cost-effectiveness of oral cancer screening programmes in a number of primary care environments was simulated using a decision analysis model. Primary data on actual resource use and costs were collected by case note review in two hospitals. Additional data needed to inform the model were obtained from published costs, from systematic reviews and by expert opinion using the Trial Roulette approach. The value of future research was determined using expected value of perfect information (EVPI) for the decision to screen and for each of the model inputs. SETTING: Hypothetical screening programmes conducted in a number of primary care settings. Eight strategies were compared: (A) no screen; (B) invitational screen--general medical practice; (C) invitational screen--general dental practice; (D) opportunistic screen--general medical practice; (E) opportunistic screen--general dental practice; (F) opportunistic high-risk screen--general medical practice; (G) opportunistic high-risk screen--general dental practice; and (H) invitational screen--specialist. PARTICIPANTS: A hypothetical population over the age of 40 years was studied. MAIN OUTCOME MEASURES: The main measures were mean lifetime costs and quality-adjusted life-years (QALYs) of each alternative screening scenario and incremental cost-effectiveness ratios (ICERs) to determine the additional costs and benefits of each strategy over another. RESULTS: No screening (strategy A) was always the cheapest option. Strategies B, C, E and H were never cost-effective and were ruled out by dominance or extended dominance. Of the remaining strategies, the ICER for the whole population (age 49-79 years) ranged from pound 15,790 to pound 25,961 per QALY. Modelling a 20% reduction in disease progression always gave the lowest ICERs. Cost-effectiveness acceptability curves showed that there is considerable uncertainty in the optimal decision identified by the ICER, depending on both the maximum amount that the NHS may be prepared to pay and the impact that treatment has on the annual malignancy transformation rate. Overall, however, high-risk opportunistic screening by a general dental or medical practitioner (strategies F and G) may be cost-effective. EVPIs were high for all parameters with population values ranging from pound 8 million to pound 462 million. However, the values were significantly higher in males than females but also varied depending on malignant transformation rate, effects of treatment and willingness to pay. Partial EVPIs showed the highest values for malignant transformation rate, disease progression, self-referral and costs of cancer treatment. CONCLUSIONS: Opportunistic high-risk screening, particularly in general dental practice, may be cost-effective. This screening may more effectively be targeted to younger age groups, particularly 40-60 year olds. However, there is considerable uncertainty in the parameters used in the model, particularly malignant transformation rate, disease progression, patterns of self-referral and costs. Further study is needed on malignant transformation rates of oral potentially malignant lesions and to determine the outcome of treatment of oral potentially malignant lesions. Evidence has been published to suggest that intervention has no greater benefit than 'watch and wait'. Hence a properly planned randomised controlled trial may be justified. Research is also needed into the rates of progression of oral cancer and on referral pathways from primary to secondary care and their effects on delay and stage of presentation.

Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer.

The objectives of this study were to investigate the tolerability of a novel high-dose chemotherapy (HDC) regimen with peripheral blood progenitor cell (PBPC) support in patients with pretreated advanced ovarian cancer and to determine the maximum-tolerated dose (MTD) of topotecan in this setting. Advanced ovarian cancer patients previously treated with platinum-based first-line therapy were enrolled. After PBPC mobilization and harvesting, patients received three consecutive cycles of HDC with PBPC support. Cycle 1 was carboplatin area under the concentration curve 20 and paclitaxel 250 mg/m(2). Cycle 2 was topotecan starting at 5 mg/m(2), dose escalated in 2 mg/m(2) increments, and etoposide 600 mg/m(2). Cycle 3 was thiotepa 500 mg/m(2). After each cycle, PBPCs were infused. Granulocyte colony stimulating factor (5 microg/kg/day) was administered until neutrophil recovery occurred. Seventeen patients were enrolled; all were safety evaluable. The most common nonhematologic toxicity was grade 3 mucositis (44%). Engraftment of PBPCs was successful in all patients after each cycle, and no treatment-related deaths occurred. Of 14 patients with measurable disease, 5 (36%) had complete responses, 2 (14%) had partial responses, and 4 (29%) had stable disease. The median progression-free and overall survivals were 7 and 18 months, respectively. The MTD of topotecan was not reached. The tolerability and activity of this regimen in patients with advanced ovarian cancer warrant further investigation.

Effects of a structured treatment algorithm on blood pressure goal rates in both stage 1 and stage 2 hypertension.

This study analysed the efficacy of an angiotensin receptor blocker-based treatment algorithm for achieving goal blood pressure (BP) in patients with stage 1 (systolic BP (SBP) 140-159 mmHg or diastolic BP (DBP) 90-99 mmHg) or stage 2 (SBP > or = 160 mmHg or DBP > or = 100 mmHg) hypertension. In this 24-week, open-label, multicentre study, patients followed a six-step algorithm until goal BP (< or = 130/85 mmHg) was attained. Initially, olmesartan medoxomil 20 mg/day was administered for 4 weeks. The regimen was modified every 4 weeks until goal BP was attained: increase olmesartan medoxomil to 40 mg/day; add hydrochlorothiazide (HCTZ) 12.5 mg/day; increase HCTZ to 25 mg/day; add amlodipine besylate 5 mg/day; increase amlodipine besylate to 10 mg/day. In patients with stage 1 hypertension, 80% (63/79) and 56% (44/79) achieved BP goals of < or = 140/90 mmHg and < or = 130/85 mmHg, respectively, with olmesartan medoxomil monotherapy (94% (74/79) and 89% (70/79) with olmesartan medoxomil/HCTZ double therapy, and 96% (76/79) and 98% (77/79) with addition of amlodipine besylate (triple therapy)). Mean SBP/DBP reductions were 16.7/11.6, 24.8/15.8, and 26.4/16.5 mmHg for mono-, double-, and triple-therapy, respectively. In patients with stage 2 hypertension, 42% (42/100) and 19% (19/100) achieved BP goals of < or = 140/90 mmHg and < or = 130/85 mmHg, respectively, with monotherapy (75% (75/100) and 54% (54/100) with double therapy, and 90% (90/100) and 81% (81/100) with triple-therapy). Mean SBP/DBP reductions in stage 2 patients were 18.4/10.0, 32.7/16.3, and 39.1/19.4 mmHg for mono-, double, and triple therapy, respectively. Overall, most patients with stage 1 or stage 2 hypertension achieved goal BP.

Cost effectiveness of photodynamic therapy with verteporfin for age related macular degeneration: the UK case.

AIM: To estimate the potential cost effectiveness of photodynamic therapy (PDT) with verteporfin in the UK setting. METHODS: Using data from a variety of sources a Markov model was built to produce estimates of the cost effectiveness (incremental cost per quality adjusted life year (QALY) and incremental cost per vision year gained) of PDT for two cohorts of patients (one with starting visual acuity (VA) of 20/40 and one at 20/100) with predominantly classic choroidal neovascular disease over a 2 year and 5 year time horizon. A government perspective and a treatment cost only perspective were considered. Probabilistic and one way sensitivity analyses were undertaken. RESULTS: From the government perspective, over the 2 year period, the expected incremental cost effectiveness ratios range from 286 000 (starting VA 20/100) to 76 000 UK pounds (starting VA 20/40) per QALY gained and from 14 000 (20/100) to 34 000 UK pounds (20/40) per vision year gained. A 5 year perspective yields incremental ratios less than 5000 UK pounds for vision years gained and from 9000 (20/40) to 30 000 UK pounds (20/100) for QALYs gained. Without societal or NHS cost offsets included, the 2 year incremental cost per vision year gained ranges from 20 000 (20/100) to 40 000 UK pounds (20/40), and the 2 year incremental cost per QALY gained ranges from 412 000 (20/100) to 90 000 UK pounds (20/40). The 5 year time frame shows expected costs of 7000 (20/40) to 10 000 UK pounds (20/100) per vision year gained and from 38 000 (20/40) to 69 000 UK pounds (20/100) per QALY gained. CONCLUSION: This evaluation suggests that early treatment (that is, treating eyes at less severe stages of disease) with PDT leads to increased efficiency. When considering only the cost of therapy, treating people at lower levels of visual acuity would probably not be considered cost effective. However, a broad perspective that incorporates other NHS treatment costs and social care costs suggests that over a long period of time, PDT may yield reasonable value for money.

There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury.

The experimental literature has shown that neurons within sub-fields of the hippocampus possess differential sensitivities to cell loss after different types of insult to the brain. In humans, after blunt head injury, differential neuronal responses between sub-fields of the hippocampus up to 72 hours after injury have been documented. But, in only a small part of the literature have data for alterations in real numbers of neurons been provided. In this study the hypothesis was tested that, after severe blunt head injury in humans, the total number of neurons within a defined volume of brain tissue differed between different sub-fields of the hippocampus and between groups of patients with differing post-traumatic survivals. Stereological methods were used to measure total cross-sectional area of sub-fields of the hippocampus taken at the level of the lateral geniculate nucleus and count numbers of neurons within each of the CA1, CA2, CA3, and CA4 sub-fields of the hippocampus in patients. The patients used in this study were categorized as follows: Group 1 (early) had survived for 1 week or less; Group 2 (late) survived 6 months or longer after fatal severe head injury; and Group 3 (controls) consisted of age-matched patients that had no history of head injury or disease prior to death. There was a significant loss in cross-sectional area in sub-fields CA3 and CA4 at 1 week or less after injury and in sub-field CA1 at 6 months and greater survival. There was no change in CA2. There was loss of neurons from within a predefined volume of brain tissue in sub-fields CA1, CA3, and CA4 one week or less after injury. But there was no loss in CA2. There was continued loss of neurons from sub-fields CA1 and CA4 between 1 week and 6 months and greater survival, but there was no loss of neurons in sub-fields CA2 and CA3 within the same period. These novel data show that after human severe head injury there is first an acute loss (1 week or less survival) of pyramidal neurons in all hippocampal sub-fields except CA2. Second, there is an ongoing loss of neurons in sub-field CA1 and, most notably, in sub-field CA4, in patients surviving for more than 6 months. However, in neither group of patients is there loss of neurons from sub-field CA2.

A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the USA and the UK.

BACKGROUND: Economic information is necessary for rational decision-making in health care. Many European countries require financial impact statements prior to drug approval, and many health care organizations in the USA consider cost-effectiveness when making formulary decisions. We report the findings and discuss the policy implications of an economic evaluation based on an international, randomized controlled trial of salvage therapy for epithelial ovarian cancer, wherein topotecan and pegylated liposomal doxorubicin (PLD) were found to have similar efficacy but differing toxicities. PATIENTS AND METHODS: Direct costs to the payer were estimated for 235 North American and 239 European trial participants who had relapsed or failed platinum-based therapy. Unit costs were obtained from national sources or previously reported economic analyses. Sensitivity analyses were also performed. RESULTS: Total cost per person in the topotecan arm was 12,325 dollars (95% CI 9445 dollars to 15,415 dollars; P >0.05) higher in the USA-based analysis and 2909 dollars (95% CI 779 dollars to 3415 dollars; P <0.05) higher in the UK-based analysis than for PLD. Pegylated liposomal doxorubicin was cost saving over a wide range of assumptions. The main differences (per person) in toxicity management following PLD compared with topotecan in Europe were for blood transfusions (1190 dollars versus 181 dollars, respectively) and hospitalizations (1197 dollars versus 280 dollars, respectively). In North America, differences were mainly for granulocyte colony stimulating factors (1936 dollars versus 419 dollars micro g, respectively), erythropoietin (3493 dollars versus 308 dollars, respectively) and blood transfusions (1346 dollars versus 140 dollars, respectively). CONCLUSIONS: Policy makers who evaluate pharmacoeconomic studies should consider international differences in health care delivery. Cost assessments based on information obtained from one country may not be relevant for policy makers in a different country.

Notes on a pilgrimage to science: a fly on the wall.

The paper is a set of reflections on the moral culture of modern biology built around the author's experience as a participant observer in two university laboratories. I draw parallels between laboratory culture and organized religion and point out practical problems in conducting scientific research. The notion that good biologists must be atheists is questioned and failures of organized religion are noted. The paper concludes with a suggestion that research ethics should be rooted in laboratory practice and must include vigorous principles of honesty and justice. Those are not requirements imposed from outside but internal requirements of the research community.

Pharmacology of cardiovascular chronotherapeutic agents.

Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people-both normotensive and hypertensive-blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustained-release pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep.

Use of newborn Girardia tigrina (Girard, 1850) in acute toxicity tests.

Acute toxicity tests, exposing Girardia tigrina to potassium dichromate (K(2)Cr(2)O(7)), showed good reproducibility. The 95% confidence intervals among tests were 0.0262+/-0.0141 g for 48-h LC(50) (N=6) and 0.0129+/-0.0078 g for 96-h LC(50) (N=5). The 96-h LC(50) for G. tigrina was below that of oligochaetes and above that of cladocera.

Giant cell arteritis mimicking a testicular tumour.

Giant cell arteritis involving the testis was identified incidentally upon orchidectomy of a right testicular mass. The mass looked like a malignant process on ultrasound. The patient also had generalised disease and was treated appropriately. Giant cell arteritis involving the bladder, prostate, uterus, and adnexa have been described before. To our knowledge, this is the first described case of giant cell arteritis affecting the testis.

The practice of discounting in economic evaluations of healthcare interventions.

OBJECTIVES: Discounting of costs in health-related economic evaluation is generally regarded as uncontroversial, but there is disagreement about discounting health benefits. We sought to explore the current recommendations and practice in health economic evaluations with regard to discounting of costs and benefits. METHODS: Recommendations for best practice on discounting for health effects as set out by government agencies, regulatory bodies, learned journals, and leading health economics texts were surveyed. A review of a sample of primary literature on health economic evaluations was undertaken to ascertain the actual current practice on discounting health effects and costs. RESULTS: All of the official sources recommended a positive discount rate for both health effects and costs, and most recommended a specific rate (range, 1% to 8%). The most frequently specified rates were 3% and 5%. A total of 147 studies were reviewed; most of these used a discount rate for health of either 0% (n = 50) or 5% (n = 67). Over 90% of studies used the same discount rate for both health and cost. While 28% used a zero rate for both health and cost, in 64% a nonzero rate was used for both. Studies where the health measure was in natural clinical units (direct) were significantly more likely to have a zero discount rate. CONCLUSION: The finding that 28% of studies did not discount costs or benefits is surprising and concerning. A lower likelihood of discounting for benefits when they are in natural units may indicate confusion regarding the rationale for discounting health effects.

Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake.

Previous clinical trials have demonstrated the important influence of ethnicity and dietary salt on the antihypertensive efficacy of drugs that block the renin angiotensin system. Angiotensin II receptor blockers are a new therapeutic entity that have not been widely studied in African American hypertensives, either alone, or in combination with other therapies such as diuretics or angiotensin converting enzyme inhibitors. We performed a pilot, prospective, open label, randomized design clinical trial to evaluate the effects of the angiotensin II receptor blocker valsartan (160 mg once a day) on systolic and diastolic blood pressure in hypertensive African Americans (n = 88) on a low salt (100 mEq Na+/day) for 2 weeks and the same diet supplemented by 100 mEq Na+ for 4 weeks. After this evaluation, while continuing the Na+ supplementation, patients were randomized to valsartan 320 mg/day (n = 28), or the addition of hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 30), or benazepril 20 mg/day to the valsartan 160 mg/day for an additional 6 weeks. Valsartan (160 mg/day) lowered blood pressure significantly in African American patients on both low salt (-6.4/-4.8 mm Hg: P < .001) and a high salt diet (-4.9/-3.8 mm Hg: P = .01). The high salt diet attenuated the antihypertensive effect slightly (1.6/1.3 mm Hg, P = not significant). When comparing the efficacy of the three randomized therapeutic regimens while on the Na+ supplement, the valsartan 160 mg/HCTZ 12.5 mg was the most effective therapy with an incremental reduction in blood pressure of -10.5/-6.9 mm Hg (P < .01), compared to valsartan 160 mg/day alone. Doubling the dose of valsartan to 320 mg incrementally lowered blood pressure by -3.8/-3.3 mm Hg (P = not significant). The least effective approach was adding benazepril 20 mg/day to valsartan 160 mg/day with no incremental reduction in systolic blood pressure and diastolic blood pressure reduction of only 1.7 mm Hg (P = not significant). We conclude that in our open label pilot study, the antihypertensive activity of valsartan is not significantly attenuated by supplemented salt diet in hypertensive African Americans. Moreover, adding a low dose of HCTZ appears to be the most effective strategy in enhancing the antihypertensive activity of this angiotensin II receptor blocker in contrast to either doubling the dose or adding an angiotensin converting enzyme inhibitor.

Critical wavelength for river meandering.

A fully nonlinear modal analysis identifies a critical centerline wave number q(c) for river meandering that separates long-wavelength bends, which grow to cutoff, from short-wavelength bends, which decay. Exact, numerical, and approximate analytical results for q(c) rely on the Ikeda, Parker, and Sawai [J. Fluid Mech. 112, 363 (1981)] model, supplemented by dynamical equations that govern the river migration and length. Predictions also include upvalley bend migration at long times and a peak in lateral migration rates at intermediate times. Experimental tests are suggested.