Long-term Observational Studies Research Articles

Composition, size, and biomass of zooplankton in large productive Florida lakes

Crustacean zooplankton data were compiled from long-term observational studies at seven large shallow Florida lakes, to determine whether there are general characteristics in regard to species composition, body size, and biomass. In particular, we examined whether patterns in body size and species richness fit empirical models developed by Stanley Dodson. The lakes included range in size from 125 to 1730 km2 and encompass mesotrophic to hyper-eutrophic conditions. We found that zooplankton biomass was strongly dominated by one species of calanoid copepod—Arctodiaptomus dorsalis. Large daphnids were absent, and Cladocera assemblages were dominated by small taxa such as Ceriodaphnia, Chydorus, and Eubosmina. The total number of species of pelagic cladocerans (8–12) was consistent with Dodson’s predictions based on lake area. The average size of crustacean zooplankton in Florida lakes is small in comparison with temperate communities. A. dorsalis is the smallest calanoid copepod in North America, and the mean length of Cladocera (0.6 mm) is consistent with Dodson’s results that size decreases from temperate to tropical zones. Total biomass of crustacean zooplankton was very low, ratios of zooplankton to phytoplankton biomass (0.01–0.1) are among the lowest reported in the literature, and the zooplankton displayed short-lasting early spring peaks in biomass. Cladocera were almost entirely absent in spring and summer. Factors known to occur in Florida lakes, which appear to explain these characteristics of biomass, include intense fish predation and high summer water temperature.

Uterine Artery Embolization for Fibroids: A Review of Current Outcomes

Since its introduction in 1995, uterine artery embolization (UAE) for fibroids has been extensively investigated. Particularly in the last 3 to 4 years, several high-quality studies assessing its outcome have been completed. Randomized trials and long-term observational studies have demonstrated that when successful, UAE can provide symptom control similar to that obtained after surgery. Although hysterectomy remains more effective in symptom control and durability, many women are seeking uterine-sparing alternatives. UAE has emerged as the leading minimally invasive treatment for fibroids: Morbidity is low and recovery rapid; serious complications are quite rare. With a few anatomical exceptions, UAE is appropriate for most patients with symptomatic fibroids who have completed childbearing. Although pregnancy is certainly possible after embolization, existing data suggest better reproductive outcomes for myomectomy in the first 2 years after treatment. The current recommendation is for myomectomy as a first choice for patients seeking to become pregnant.

PWE-079 Use of antisecretory medication after antireflux surgery for patients with gastro-oesophageal reflux disease: a systematic review of non-randomised studies

<h3>Introduction</h3> Although antireflux surgery is effective for selected patients with gastro-oesophageal reflux disease (GERD), some patients require further antireflux medication after a variable period. We have previously reported that 14% (95%CI 9% to 20%) of patients require antisecretory medication after antireflux surgery (ARS), based on a meta-analysis of 18 RCTs.1 Since most surgical studies examining the efficacy of ARS are not randomised, we aimed to investigate the need for further ARM after ARS in recent non-randomised studies. <h3>Methods</h3> MEDLINE and EMBASE databases were searched from 2005 up to Oct 2009 for published, English-language, non-randomised studies investigating the efficacy of ARS for GERD in adults, and reporting the use of ARM after ARS. The proportions of patients using ARM after ARS were sample size weighted and pooled by applying a random-effects model using StatsDirect 2.7.2®. <h3>Result</h3> In total, 24 clinical studies met inclusion criteria with follow-up ranging from 0 to 3 months to &gt;10 years and most were single arm observational studies. Some studies reported data for more than one time point. Most surgical interventions were fundoplication, while a few studies only stated “anti-reflux surgery”. When all studies were pooled, regardless of the follow-up time point and only considering the last measured data for the same study, 20% (95% CI 13% to 28%) of patients required ARM after ARS (25 arms, n=7739). The corresponding data for the use of PPIs were 18% (11–25%, 20 arms, n=5994). When subgroup analyses were performed for different follow-up periods, the proportions of patients who required ARM after ARS were 15% (8–23%, 5 arms, n=1680), 24% (12–37%, 7 arms, n=1301), 18% (9–30%, 12 arms, n=5929), and 27% (18–37%, 5 arms, n=1447) for &lt;1 year, 1–3 years, 3–5 years, and 5–10 years, respectively. The corresponding data for the use of PPIs were 14% (6–24%, 4 arms, n=836), 36% (18%–56%, 3 arms, n=225), 12% (3–25%, 9 arms, n=3572), and 21% (15–28%, 5 arms, n=1447). <h3>Conclusion</h3> After antireflux surgery, 20% of patients still require antireflux medication in non-randomised studies, and this proportion increases with the duration of follow-up to 27% after 10 years. This figure from non-randomised studies, which is higher than that from randomised studies, is probably more representative of the unmet need in clinical practice. However, some important issues remain unanswered, including the reasons for taking ARM after ARS, and the effect of loss to follow-up in long-term observational studies. Furthermore, how best to manage reflux patients who fail surgical treatment requires further investigation.

Cyclophosphamide and Lupus Nephritis: When, How, For How Long?

Ever since the introduction of cyclophosphamide (CY), the management of lupus nephritis has dramatically changed, and its prognosis has greatly improved. Based on randomized controlled trials and long-term observational studies, pulse therapy with CY in combination with methyl-prednisolone (MP) is the "gold standard" of therapy for severe lupus. The realization of the significant gonadal toxicity intensified the efforts for the development of alternative immunosuppressive agents. In a large, randomized controlled trial, newer agents such as mycophenolate mofetil (MMF) have demonstrated comparable efficacy and less toxicity for moderately severe disease. To date, combinations of monthly pulses of CY with MP remain the gold standard for the induction of remission in severe lupus. For maintenance, less toxic agents such as azathioprine or MMF are equally effective and are routinely used in the current therapy of lupus.

Donepezil: A Review of Pharmacological Characteristics and Role in the Management of Alzheimer Disease

Donepezil is a potent, selective, noncompetitive, and rapidly reversible inhibitor of acetylcholinesterase (AChEI) licensed for the treatment of Alzheimer disease (AD); and is the first and only AChEI licensed for the treatment of severe AD. Its efficacy as monotherapy, or in combination with the NMDA-agonist, memantine, has been documented in several randomised double-blind, placebo-controlled, short-term clinical trials, as well as long-term extension trials and observational studies. Donepezil is a well tolerated drug that is generally safe as demonstrated even in patients with multiple co-morbidities receiving polypharmacy. It has been shown that donepezil improves cognition and global function in patients with mild-to-moderate AD; and long-term efficacy is maintained for up to 50 weeks. There is a dose-response relationship, with higher doses more likely to produce symptomatic benefit. Furthermore, donepezil-treated patients may improve cognitively and show global clinical improvement in all disease stages, including severe AD. Less consistent results in all disease stages were obtained on measures of function and behavior, and observations of mood. No effect on transition to AD has been found in long-term, randomized clinical trials in mild cognitive impairment (MCI). Cost-effectiveness of the treatment has been questioned by one long-term open-label societal study of 2-years duration. This study reported modest improvement of cognition but no statistically significant benefits during donepezil treatment as compared to placebo, in terms of rates of institutionalization and progression toward greater disability. However, there is a need for further research on clinically meaningful outcomes and treatment benefits favored by patients and caregivers, which are traditionally not defined as outcomes in clinical trials. Likewise, we need to know how to select responders, what is an optimal AChE inhibition particularly during the long-term treatment, in which patients the dosage should be increased for a sustained benefit, what is the optimal duration of treatment and when is meaningful to stop the treatment. After almost two decades of donepezil use in everyday clinical practice these issues are still unresolved.

Immunoadsorption for systemic lupus erythematosus

Abstract Immunoadsorption (IAS) with various methods is used as a rescue therapy in severely ill SLE patients who are refractory to conventional therapeutic procedures. The method aims at the rapid and extensive removal of pathogenic immunocomplexes (IC) and (auto-) antibodies (Abs). Long-term observational studies suggested efficacy and have not seen an increase in the risk of infections (as were seen in other extracorporeal procedures). Unfortunately, prospective, randomized controlled trials (RCT) are lacking. Recently, biologicals aiming at TNF-blockade or B-cell depletion have been used to treat severe SLE: They are easier to apply since they do not necessitate additional (expensive) hardware or specially trained staff. While there is emerging evidence for efficacy from uncontrolled observations, no RCT could so far demonstrate benefit in SLE. Under these circumstances, IAS still has a role in treating severe SLE, when other therapies are not effective enough or are contraindicated (as in pregnancy). These data are reviewed and illustrated in the case of a pregnant lupus patient with nephrotic syndrome.

Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy

The present review aims to examine the effect of specific drugs on long-term outcome of pulmonary arterial hypertension (PAH), to critically review the available data, and to derive useful information for daily patient care. PAH is an intrinsic disease of the pulmonary circulation with a malignant evolution as a consequence of progressive right heart failure. Without specific therapy, median survival is only 2.8&emsp14;yrs. The intravenous prostacyclin analogue epoprostenol is the only treatment with a demonstrated effect on survival, observed during a single 12-week randomised placebo-controlled trial. Three long-term observational studies have also shown that median survival is raised above 6&emsp14;yrs with this therapy. Subcutaneous treprostinil appears to have similar beneficial effects on survival, as reported in two long-term observational studies. This is not the case for inhaled iloprost, as shown in one study in which a high proportion of patients needed the addition of, or the switch to, another therapy. Among the oral agents, long-term data have only been published for bosentan. The three studies including patients from expert centres also showed very good survival data, but again with a broad use of combination therapy. In less expert hands, with limited access to more complex therapies, reported survival seems much worse. In these studies, baseline New York Heart Association class and 6-min walk distance are repeatedly shown to be important predictors of survival. Finally, there is emerging data that prostanoid therapy results in a tendency to normalise C-reactive protein levels, a factor associated with improved long-term outcomes.

The Need for a Children's Oncology Group–Oriented Approach to Advance the Care of Children with Idiopathic Nephrotic Syndrome

diopathic nephrotic syndrome (INS) affects 16 per 100,000 children, making this condition one of the most common childhood kidney diseases. Because of the significant com- plications associated with INS and its treatments in children, childhood INS remains a daunting challenge for children, fam- ilies, and medical professionals. Amazingly, the approach to childhood INS today is still based on decades-old pivotal stud- ies that were impressive in scope but have limited applicability to the clinical challenges faced by pediatric nephrologists to- day. These foundational studies began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children (ISKDC) (1). From 1967 to 1974, 521 children with new-onset INS underwent renal biopsies and standard prednisone treatment to demonstrate that normaliza- tion of urine protein excretion with 8 wk of corticosteroid therapy is predictive of minimal-change nephrotic syndrome (2). As a result, pediatric nephrologists began using the initial therapeutic response to glucocorticoids to guide the subsequent evaluation and therapy for children who present with INS. This sentinel work of the ISKDC was followed by a series of studies by the Arbeitsgemeinschaft fur Padiatrische Nephrologie, which together form the basis for modern practice treatment of children with INS (3-5). Of note, these landmark studies are also almost 20 yr old, but the clinical characteristics and chal- lenges of children who present with INS have clearly changed in recent decades. For example, the incidence of FSGS in chil- dren with INS has increased dramatically (6); children in the United States have a rapidly increasing prevalence of obesity and type 2 diabetes, which may be exacerbated by our standard treatments with glucocorticoids (7); and the importance of de- mographic status and treatment compliance in patient out- comes is being increasingly recognized (8). In 2008, a survey regarding treatment of childhood INS among North American pediatric nephrologists at 10 US cen- ters was performed. That survey highlighted significant dispar- ities among practitioners, including wide practice variations in even the most fundamental aspects of care, such as the man- agement of initial presentations, relapses, and steroid resistance in children with INS (9). In this context, the North American Children's Nephrotic Syndrome Consensus Conference was convened to develop updated evidence- and opinion-based recommendations for the evaluation and treatment of children with INS for North American pediatric nephrologists (10). In that consensus conference report, only a limited number of treatment recommendations could be based on class 1 evidence; recommendations related to extent of evaluation, monitoring for complications, and treatment for steroid-dependent and steroid-resistant NS almost all were based on small case series and expert opinion. Of note, despite the 344 published original investigations reviewed during this process, only three of the 86 articles cited in that consensus conference report involved 10 yr of outcome follow-up in children with INS. This sober- ing reality emphasizes the value of the study of Kyrieleis et al. (11) in this month's CJASN, which addresses the long-term outcome of frequently relapsing minimal-change nephrotic syndrome in children and focuses on the effectiveness of con- tinued immunosuppression and the complications of these agents in this population. In this report, at least 10 yr of fol- low-up is provided for all 15 patients with steroid-responsive INS that presented in childhood. All had at least one relapse after 16 yr of age, and the long follow-up offers insights into the ongoing treatment responsiveness in these children. Although this article indicates that corticosteroid responsiveness may persist for many years in some children, particularly in combi- nation with second-line agents such as calcineurin inhibitors, complications are common and the risk-benefit ratios of treat- ments are unexplored. Although this report is only observa- tional, it does reinforce the value and usefulness of detailed long-term observational studies of these children. Because the vast majority of our patients will survive to adulthood, there is a distinct need for studies of the long-term outcomes (and

DOUBLE PROTECTION: Reaching Accord on the Ethical Conduct of Child Observational Research

From Bernardino Ramazzini’s visits to seventeenth-century craftsmen’s worksites—where he made observations that earned him the title of “father of occupational medicine”—to modern-day research leading to bans on public smoking, observational studies have improved and enhanced environmental health. Such studies involve observing people’s everyday lives, defining the characteristics of their environments, and determining whether any risks arise from activities within the context of those environments. Modern environmental observational studies, including the recently launched National Children’s Study, also measure environmental compounds and their metabolites in people’s bodies while assessing sources and routes of exposure so that the appropriate agencies can initiate reduction strategies if high exposures are seen. Generally, an observational study is conducted without the observer intervening with research subjects to avoid undermining research goals. However, strict adherence to this practice could create significant ethical concerns, particularly when a vulnerable subject such as a child is at risk for harm. Misunderstandings and disagreements about how those concerns should be addressed in children’s observational exposure studies have forced researchers and policy makers to more precisely—and now possibly successfully—define what constitutes a scientifically rigorous and ethical study.

What’s new in clinical trials in lupus?

Systemic lupus erythematosus is associated with substantial morbidity and involves major organs including the kidneys and the CNS. Based on randomized, controlled trials and long-term observational studies, cyclophosphamide in combination with glucocorticosteroids is considered the ‘gold standard’ therapy for severe lupus. However, cyclophosphamide therapy is associated with relapses and significant toxicity. Recent trials have explored the efficacy of old, widely used therapies, including the steroid-sparing effects of methotrexate, the ability of cyclosporine or glucocorticoids to prevent lupus flares and the use of azathioprine as maintenance therapy. As for newer agents, mycophenolate mofetil has been demonstrated to be at least as efficacious as, and less toxic than, cyclophosphamide as induction therapy for moderately severe proliferative lupus nephritis. Rituximab (anti-CD20 mAb) and tacrolimus have also been demonstrated to be effective in immunosuppressive-resistant cases but need to be tested in...

Antipsychotic Medication in Children and Adolescents: A Descriptive Review of the Effects on Prolactin Level and Associated Side Effects

This review reports the incidence of hyperprolactinemia, its relationship with genotype, and prolactin-related side effects in children and adolescents treated with antipsychotics. Data on prolactin levels were available for haloperidol, pimozide, risperidone, olanzapine, clozapine, ziprasidone, and quetiapine. Twenty-nine studies were selected after a literature search in the English Medline/Embase/Psychinfo/EBM databases (1965 to August, 2008). All antipsychotics, except clozapine, ziprasidone, and quetiapine, increase the mean prolactin level from baseline values of 8.0 ng/mL to 25-28 ng/mL after 4 weeks of treatment (reference range 0-15 ng/mL). The most and best data are available for risperidone. Five risperidone studies (n = 577) show an increase of prolactin level from 7.8 ng/mL to 17.7 ng/mL after 1 year of treatment, and two risperidone studies (n = 60) show an increase from 7.4 ng/mL to 24.9 ng/mL after 2 years of treatment. Aggregated over all antipsychotics, prolactin-related side effects, such as gynecomastia, galactorrhea, irregular menses, and sexual dysfunction, were reported by 4.8% of the children and adolescents. No data are available on bone mineral density in relation to antipsychotic-induced hyperprolactinemia in children and adolescents. Prolactin levels may be influenced by the genetic differences that influence prolactin metabolism and D2 dopamine receptor density. Persistent elevation of prolactin for periods up to 2 years has been documented in maintenance treatment with risperidone. Very limited long-term data of pimozide, olanzapine, and quetiapine prohibit drawing conclusions for these antipsychotics. Systematic long-term observational studies, including specific questionnaires as well as physical examination, are needed to investigate prolactin-related side effects of antipsychotic treatment in children and adolescents.

Health effects of trans-fatty acids: experimental and observational evidence

Growing evidence indicates that trans-fatty acids (TFA) adversely affect cardiovascular health. As part of the World Health Organization (WHO) Scientific Update on TFA, we reviewed the evidence for effects of TFA consumption on coronary heart disease (CHD). We searched Medline publications examining TFA consumption and CHD risk factors or outcomes, emphasizing results of studies in humans. We evaluated and synthesized evidence from both controlled feeding trials evaluating risk factors and long-term observational studies evaluating risk factors or clinical outcomes, each of which have complementary strengths and limitations, to enable the most robust and reliable inferences of effects. The effects of TFA consumption on risk factors most consistently seen in both controlled trials and observational studies included adverse lipid effects (for example [upward arrow] low-density lipoprotein cholesterol, [downward arrow] high-density lipoprotein cholesterol (HDL-C), [upward arrow] total/HDL-C ratio), proinflammatory effects (for example [upward arrow] tumor necrosis factor-alpha activity, [upward arrow] interleukin-6, [upward arrow] C-reactive protein) and endothelial dysfunction. These effects were most prominent in comparison with cis unsaturated fats; adverse effects on total/HDL-C and endothelial function were also seen in comparison with saturated fatty acids (SFA). TFA may also worsen insulin sensitivity, particularly among individuals predisposed to insulin resistance; possible effects on weight gain and diabetes incidence require further confirmation. Five retrospective case-control studies and four prospective cohort studies demonstrated positive associations between TFA consumption and CHD events. A meta-analysis of prospective studies indicated 24, 20, 27 and 32% higher risk of myocardial infarction (MI) or CHD death for every 2% energy of TFA consumption isocalorically replacing carbohydrate, SFA, cis monounsaturated fatty acids and cis polyunsaturated fatty acids, respectively. The differential effects of specific TFA isomers may be important but are less well established. The available evidence indicates that trans-18:1 and particularly trans-18:2 isomers have stronger CHD effects than trans-16:1 isomers. The limited data suggest that the experimental effects of ruminant and industrial TFA are similar when consumed in similar quantities, but very few persons consume such high levels of ruminant TFA, and observational studies do not support adverse CHD effects of ruminant TFA in amounts actually consumed. Controlled trials and observational studies provide concordant evidence that consumption of TFA from partially hydrogenated oils adversely affects multiple cardiovascular risk factors and contributes significantly to increased risk of CHD events. The public health implications of ruminant TFA consumption appear much more limited. The effects of specific TFA isomers require further investigation.

Modifiable Midlife Risk Factors for Late-Life Cognitive Impairment and Dementia.

The baby boom generation is approaching the age of greatest risk for cognitive impairment and dementia. There is growing interest in strategies to modify the environment in midlife to increase the probability of maintaining cognitive health in late life. Several potentially modifiable risk factors have been studied in relation to cognitive impairment and dementia in late life, but methodological limitations of observational research have resulted in some inconsistencies across studies. The most promising strategies are maintaining cardiovascular health, engagement in mental, physical, and social activities, using alcohol in moderation, abstaining from tobacco use, and following a heart-healthy diet. Other factors that may influence cognitive health are occupational attainment, depression, personality, exposure to general anesthesia, head injury, postmenopausal hormone therapy, non-steroidal anti-inflammatory medications, and nutritional supplements such as antioxidants. Some long-term observational studies initiated in midlife or earlier, and some randomized controlled trials, have examined the effects of specific cognitive health promotion behaviors in midlife on the risk of cognitive impairment in late life. Overall, these studies provide limited support for risk reduction at this time. Recommendations and challenges for developing effective strategies to reduce the burden of cognitive impairment and dementia in the future are discussed.

Impact of Different Bariatric Surgical Procedures on Insulin Action and β-Cell Function in Type 2 Diabetes

The prevalence of obesity appears to have reached a plateau in the U.S. between 2003 and 2007 (1), but the obesity epidemic is still rampant in many other countries—especially in the developing world (2)—in adults as well as children (http://www.who.int/topics/obesity/en/). A recent analysis of a large prospective cohort of individuals 50–71 years old (3) has generated a precise dose-response gradient for the positive association of BMI and relative risk of death independent of other risk factors (especially smoking and preexisting disease, which cause weight loss). Yet, long-term observational studies have generally found that weight loss, whether spontaneous or intentional, is associated with increased, rather than decreased, overall mortality (rev. in 4). Lifestyle intervention (diet and exercise), behavioral management, and drug therapy for obesity deliver a degree of weight loss that is usually modest (and therefore unattractive to patients) and short-lived (6 months to 1 year at best) and carry considerable side effects. Moreover, despite the attenuation of risk factors such as diabetes and dyslipidemia, trial evidence for an effect of these weight-control approaches on reducing cardiovascular disease or mortality is still lacking (rev. in 5). On the other hand, and perhaps as a consequence, surgery for the treatment of severe obesity is gaining increasing favor. The annual U.S. frequency of hospital discharges that included bariatric surgery increased sevenfold (from 3.5 to 24.0 per 100,000) between 1996 and 2002 (6). According to a review of 85,048 morbidly obese patients (7), early (≤30 days) and late (30 days to 2 years) mortality rates for bariatric surgery trend downward (0.28 and 0.35%, respectively). Surgical treatment of massive obesity is being extended to adolescents, seemingly with similar success and risk rates as in adults (8–10). Recently, the 10.9-year follow-up of the Swedish Obese Subjects Study reported a 30% risk reduction for …

Novel approaches in management of immune thrombocytopenia

Platelets play the key role in primary haemostasis. The number of platelets that can be recruited for these first steps of haemostasis is important, as platelets maintain vascular integrity. Therefore severe thrombocytopenia is associated with a high risk for bleedings. The overall incidence of chronic autoimmune thrombocytopenia (cAITP) is 1 to 10 per 100 000 in industrialized countries. Like most other autoimmune disorders, cAITP is more common among adults, and thereby women are more often affected than man. It is relatively benign and rarely requires treatment. Furthermore, most treatment modalities are associated with severe adverse effects that may outweigh the benefits. Therefore, currently treatment is considered appropriate only for symptomatic patients and for those at high risk of bleeding, either because of a surgical procedure or because of very low platelet counts. Short-term treatment aims to increase platelet counts in patients with acute bleeding symptoms or in those undergoing surgery. Long-term treatment may be considered to increase the quality of life, if patients are affected by low platelet counts in the form of bleeding or anxiety. Recently, two new substances have been shown to increase platelet counts in cAITP, romiplostim and eltrombopag. Both bind to the thrombopoietin receptor thereby inducing an increase of platelet formation. Remarkably, the rate of treatment success was independent of any stratification modalities like previous response to drugs or splenectomy, and was associated with rather few and mild adverse effects. Further, it was previously assumed that thrombopoiesis is already turned on to compensate increased platelet sequestration in cAITP. The treatment success shows that thrombopoiesis can be increased to enhance platelet production, strongly supporting impaired thrombopoiesis in cAITP. It is likely that romiplostim and eltrombopag will significantly add to the treatment armaments for bridging certain situations of increased risk of bleeding in cAITP, mainly if corticosteroids are contraindicated, or for non-responders to first-line treatment modalities. Their role in long-term treatment and in deferring splenectomy will be determined by their price and foremost by their proven safety in long-term observational studies.

Impact of hormone therapy for women aged 35 to 65 years, from contraception to hormone replacement

Midlife women (aged 35-65 years) present a complex combination of clinical challenges and health care opportunities. To meet these issues effectively, recognition of the various phases of the entire menopausal transition is necessary, because each possesses unique biological properties underlying phase-specific clinical presentations. The aim of this article is to inform health care decisions by defining the endocrine, metabolic, and clinical consequences of therapeutic inaction or intervention at each stage of the midlife experience. Using PubMed, MEDLINE was searched for age- and phase-specific publications about ovarian function and corresponding clinical manifestations in women aged 35 to 65 years. Large, long-term longitudinal prospective, case-control, and observational studies were selected for inclusion. Results of the Framingham Heart Study, Study of Women's Health Across the Nation, Nurses' Health Study (NHS), and Women's Health Initiative (WHI), as well as materials from the World Health Organization and American College of Obstetricians and Gynecologists, were obtained from the relevant groups' Web sites in 2008. Synthesis of the data acquired, particularly the confirmatory and contrasting elements displayed in the WHI and NHS publications, leads to a set of guiding principles whereby individualized phase-specific management strategies may be safely employed. These include the value of weight control and exercise; use of specific nonhormonal therapies for defined indications; definition of strict inclusion/exclusion criteria; and individualization of timing, regimen, dosage, and portal of entry for possible hormone therapy. An evidence-based, restrictive inclusion/exclusion strategy can be used to maximize benefits and minimize risks for this large, growing, and health-conscious but increasingly vulnerable population.

Invasive plant architecture alters trophic interactions by changing predator abundance and behavior

As primary producers, plants are known to influence higher trophic interactions by initiating food chains. However, as architects, plants may bypass consumers to directly affect predators with important but underappreciated trophic ramifications. Invasion of western North American grasslands by the perennial forb, spotted knapweed (Centaurea maculosa), has fundamentally altered the architecture of native grassland vegetation. Here, I use long-term monitoring, observational studies, and field experiments to document how changes in vegetation architecture have affected native web spider populations and predation rates. Native spiders that use vegetation as web substrates were collectively 38 times more abundant in C. maculosa-invaded grasslands than in uninvaded grasslands. This increase in spider abundance was accompanied by a large shift in web spider community structure, driven primarily by the strong response of Dictyna spiders to C. maculosa invasion. Dictyna densities were 46-74 times higher in C. maculosa-invaded than native grasslands, a pattern that persisted over 6 years of monitoring. C. maculosa also altered Dictyna web building behavior and foraging success. Dictyna webs on C. maculosa were 2.9-4.0 times larger and generated 2.0-2.3 times higher total prey captures than webs on Achillea millefolium, their primary native substrate. Dictyna webs on C. maculosa also captured 4.2 times more large prey items, which are crucial for reproduction. As a result, Dictyna were nearly twice as likely to reproduce on C. maculosa substrates compared to native substrates. The overall outcome of C. maculosa invasion and its transformative effects on vegetation architecture on Dictyna density and web building behavior were to increase Dictyna predation on invertebrate prey >/=89 fold. These results indicate that invasive plants that change the architecture of native vegetation can substantially impact native food webs via nontraditional plant --> predator --> consumer linkages.

Randomized Controlled Trials of Proton-Pump Inhibitors in Nighttime GERD

Purpose: To assess heterogeneity in enrollment criteria, methodology and methodological quality, and outcomes across randomized-controlled clinical trials (RCTs) evaluating the efficacy of proton-pump inhibitors (PPIs) in controlling nighttime symptoms of gastroesophageal reflux disease (GERD). Methods: MEDLINE and EMBASE databases from 1990 to June 2007 were searched. Studies were included if the design was a RCT, at least one treatment arm was PPI, the subjects were adults with nighttime GERD, and nighttime symptoms were assessed. The methodological quality of trials was evaluated using the score devised by Jadad et al (ranging from 1 = low to 5 = high). We also assessed nighttime criteria used for patient enrollment, nighttime outcomes measured, and the nighttime definition used. Results: Thirty-two RCTs compared the efficacy of PPI with placebo only (N = 7), H2-receptor antagonist only (N = 12), another PPI only (N = 11) or both placebo and H2-receptor antagonist (N = 2) in controlling nighttime GERD. Methodological quality of trials was high with 28 of the 32 trials attaining a Jadad score of at least 3 points. Source of data collection was patient daily diaries across all studies. The majority of studies assessed nighttime symptoms as a secondary outcome; erosive esophageal healing was usually the primary endpoint. Most studies assessed efficacy at 8 weeks or less; only 3 studies measured the long-term efficacy of PPI (pantoprazole [N = 2] and rabeprazole [N = 1]) for a year. Criteria for enrolling nighttime GERD patients (frequency and/or severity of nighttime symptoms) lacked consistency. Thirty studies (94%) assessed nighttime heartburn; few studies evaluated overall nighttime symptoms (N = 4) and only one study evaluated regurgitation as an independent outcome. Nighttime heartburn outcomes measured were percentage of patients without nighttime heartburn (N = 18), percentage of heartburn-free nights (N = 15), heartburn severity score (N = 11) or time to heartburn relief (N = 6). The time window for the assessment of nighttime symptoms was reported in only 3 studies (9%) and was not based on specific hours but on sleep or posture (retiring or lying down to sleep). Conclusion: RCTs of PPI therapy in nighttime GERD are of high methodological quality but are heterogeneous with respect to their definition of nighttime symptoms and outcomes. Consensus on diagnostic criteria for nighttime GERD would be anticipated to increase generalizability of results and guide the diagnosis and management of nighttime symptoms. Long-term observational studies may be helpful in translating the efficacy of PPI observed in clinical trials to real-world patients.

Rationale for low-dose systemic hormone replacement therapy and review of estradiol 0.5 mg/NETA 0.1 mg

The menopausal transition is associated with several symptoms, for which both non-pharmacological and pharmacological measures are available to provide relief. However, present knowledge indicates that the former is not highly effective, and that the latter, in terms of systemic oestrogen and progestogen-based hormone replacement therapy (HRT), although being effective (e.g. on vasomotor symptoms, bleeding control, bone mineral density, vaginal atrophy and quality of life), can be associated with some caveats. Amongst these are an increased risk for coronary heart disease, breast cancer, venous thromboembolism and stroke. In recent years, literature has indicated a dose dependency for HRT on some of the caveats, hence authorities (Food and Drug Administration, and the European Medicines Agency) and menopause societies (International Menopause Society and North American Menopause Society) now recommend that women deemed in need of HRT should receive the lowest possible dose without compromising the effect of symptom relief. Estradiol 0.5 mg/norethisterone acetate (NETA) 0.1 mg, despite being a lower dose than conventional hormones, is a compound, among a few other low-dose options, that can be used in such therapy. As a first-line oral option, it has demonstrated its effectiveness (which seems comparable to other compounds), with high tolerability and, apparently, no safety concerns, in a 6-month study. Further long-term clinical trials and observational studies are mandatory in order to capture any potential harm as well as to elucidate this compound's full potential. Following a thorough literature search using PubMed and MEDLINE from the earliest publication dates through to January 2008, including results from various types of clinical trials and statements on HRT, we review the rationale for these recommendations. We also review the effects and safety of a novel 'ultra-low-dose' oral continuous combined HRT tablet, estradiol 0.5 mg/NETA 0.1 mg.

Long-term outcomes after liver transplantation in children

The goal of this review is to summarize new knowledge as it relates to adherence to medical regimen, posttransplant growth, posttransplant renal dysfunction and late allograft dysfunction in pediatric liver transplant recipients. Nonadherence is perhaps the most important predictor of rejection episodes in long-term pediatric liver transplant survivors. Health-related quality of life may independently correlate with nonadherence to medical regimen. Nephrotoxicity related to calcineurin inhibitor use remains a frequent occurrence. Improved outcome will depend on trials that stratify immunosuppression based on the risk for development of posttransplant renal dysfunction. Among pediatric liver transplant recipients, late graft loss is uncommon, in part because most children do not undergo liver transplantation for diseases that recur in the allograft. Liver transplant recipients and their families face the challenge of maintaining graft function while minimizing long-term immune and nonimmune complications related to immunosuppressive medications. Gaps in knowledge remain with respect to long-term outcomes in pediatric liver transplantation and research will require not only translational efforts and clinical trials but also longitudinal and long-term observational studies to permit the recognition of emerging trends as the cohort ages.