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PREMISE Rhizomatous growth characterizes numerous taxa among vascular plants. While abundant information exists on nutrient sharing and demography, the question of how these metameric organisms move water through their bodies remains largely unstudied. Moreover, we lack an understanding of the evolutionary implications of rhizomatous growth across vascular plants. Here, we examine these questions by investigating the effects of rhizomatous growth and vascular construction on whole-plant hydraulic function. METHODS In five terrestrial fern species with diverse vascular construction, we used microCT and bright-field microscopy to examine basic vascular construction across nodes. These data were integrated with measurements of stomatal conductance under rooted and uprooted conditions to relate vascular construction and hydraulic architecture to leaf water status. RESULTS Similar to phytomers of woody seed plants, nodal regions in rhizomatous ferns are areas of hydraulic resistance. While the investigated species are somewhat hydraulically integrated along their rhizomes, hydraulic conductivity drops at nodes and stomatal conductance declined sharply when nodes were locally uprooted. Together, our data suggest that nodes are chokepoints in axial water movement along the rhizome. CONCLUSIONS Nodal chokepoints decrease hydraulic integration between phytomers. At the same time, chokepoints may act as ‘safety-valves’, hydraulically localizing each phytomer—potentially decreasing embolism and pathogen spread—suggesting a potential tradeoff in the principal construction of the fern rhizome. Moreover, we propose that shoot-borne roots (homorhizy) and the prostrate habit of rhizomatous ferns decrease the hydraulic and structural burdens that upright plants typically incur. The absence of these hydraulic and structural demands may be one reason many rhizomatous plants lack, or have minimally developed, secondary xylem.

Vascular plants account for 93% of Earth's terrestrial flora. Xylem and phloem, vital for transporting water and nutrients through the plant, unite this diverse clade. Three-dimensional arrangements of these tissues (vascular architecture) are manifold across living and extinct species. However, the evolutionary processes underlying this variation remain elusive. Using ferns, a diverse clade with multiple radiations over their ca 400-million-year history, we synthesized data across 3339 species to explore the tempo and mode of vascular evolution and to contextualize dynamics of phenotypic innovation during major fern diversification events. Our results reveal three paradigm shifts in our understanding of fern vascular evolution. (i) The canonical theory on the stepwise and unidirectional evolution of vascular architecture does not capture the complexities of character evolution among ferns. Rather, a new model permitting additional transitions, rate heterogeneity and multiple reversions is more likely. (ii) Major shifts in vascular architecture correspond to developmental changes in body size, not regional water availability. (iii) The early Carboniferous radiation of crown-group ferns was characterized by an explosion of phenotypic innovation. By contrast, during the Cretaceous and Cenozoic rise of eupolypods, rates of vascular evolution were dramatically low and seemingly decoupled from lineage diversification.

Background Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF. Methods the multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for left-truncation. the Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors. Results the cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3-3.7) and III (HR 4.0; 95% CI: 2.8-5.7) while, with redefined cut-offs, the corresponding HRs were 2.7 (95% CI: 1.8-4.0) and 5.8 (95% CI: 4.0-8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5-2.9) and lung cancer (HR 2.6; 95% CI: 1.3-4.9). Conclusions EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients., Boehringer IngelheimBoehringer Ingelheim, The EMPIRE registry is supported by a grant from Boehringer Ingelheim (since 2014). the sponsor did not have any involvement in the collection, analysis, and interpretation of the data or in the writing of or commenting on this manuscript

Immortal time occurs when study subjects’ person-time is misclassified. For example, if exposure is assigned over time, but treated as a binary “ever-exposed” variable, subjects in the exposed group are “immortal” prior to their exposure. We describe immortal time and the context in which it introduces bias and describe several approaches to avoid immortal time bias via design or mitigate it through analysis. Several authors have described examples of immortal time bias in clinical epidemiology, pharmacoepidemiology, and perinatal epidemiology. Solutions to immortal time bias include analyses that appropriately account for time-varying exposure, and design solutions that align exposure with the start of follow-up. Immortal time bias is pervasive in epidemiology. It can cause substantial bias. It is, however, easily avoided and can be controlled using appropriate analytic and design strategies.

Polyploidy and hybridization are important processes in seed-free plant evolution. However, a major gap lies in our understanding of how these processes affect the evolutionary history of high-ploidy systems. The heterosporous lycophyte genus Isoetes is a lineage with many putative hybrids and high-level polyploid taxa (ranging from tetraploid to dodecaploid). Here, we use a complex of western North American Isoetes, to understand the role of hybridization and high-level polyploidy in generating and maintaining novel diversity. To uncover these processes, we use restriction-site associated DNA sequencing (RADseq), multiple alleles of a single low-copy nuclear marker, whole plastomes, cytology (genome size estimates and chromosome counts), and reproductive status (fertile or sterile). With this dataset, we show that hybridization occurs easily between species in this complex and is bidirectional between identical, but not different, cytotypes. Furthermore, we show that fertile allopolyploids appear to have formed repeatedly from sterile homoploid and interploid hybrids. We propose that low prezygotic reproductive barriers and a high frequency of whole-genome duplication allow for high-level polyploid systems to generate novel lineages, and that these mechanisms may be important in shaping extant Isoetes diversity.

While a considerable amount of data exists on the link between xylem construction and hydraulic function, few studies have focused on resistance to drought-induced embolism of primary vasculature in herbaceous plants. Ferns rely entirely on primary xylem and display a remarkable diversity of vascular construction in their rhizomes, making them an ideal group in which to examine hydraulic structure-function relationships. New optical methods allowed us to measure vulnerability to embolism in rhizomes, which are notoriously difficult to work with. We investigated five fern species based on their diverse xylem traits at the cellular, histological, and architectural levels. To link below- and above-ground hydraulics, we then measured leaf-stem vulnerability segmentation. Overall, rhizome vulnerability to embolism was correlated most strongly with cellular but not histological or architectural traits. Interestingly, at P6-12 , species with increased architectural dissection were actually more vulnerable to embolism, suggesting different hydraulic dynamics at low compared to high percent embolism. Importantly, leaves fully embolize before stems reach P88 , suggesting strong vulnerability segmentation. This is the first study to explore the functional implications of primary vascular construction in fern rhizomes and leaf-stem vulnerability segmentation. Strong segmentation suggests that leaves protect perennial rhizomes against severe drought stress and hydraulically induced mortality.

Almost fifty years ago Dr. Rolla M. Tryon investigated the patterns of neotropical fern diversity and discovered that sites of exceptional richness and endemism are found in five predominantly montane regions. Here, we revisit these sites with the aid of contemporary methodologies. We integrate phylogenetic, ecological, climatic, and occurrence data to better understand what factors contribute to the patterns of fern diversity throughout the neotropics. With this dataset we are able to reassess Tryon's neotropical hotspots fifty years later and take one step closer to understanding the processes governing the distribution of fern species. We recover six hotspots of neotropical species richness and endemism that closely mirror those delineated by Tryon. Like Tryon, we find that hotspots are found predominantly in montane regions with more climatic space compared to surrounding areas. Patterns of species richness and lineage diversification can largely be explained by the extent of available habitats, especially in association with montane ecosystems. We also show that patterns of species assemblages across the neotropics are largely dictated by distance and elevation. In synthesis, we propose that, in addition to migration and persistence of relictual lineages, patterns of species richness and endemism in the neotropics are driven by in situ speciation in montane regions.

SummaryPolyploidy and hybridization are important processes in the evolution of spore-dispersed plants. Few studies, however, focus these dynamics in heterosporous lycophytes, such as Isoëtes, where polyploid hybrids are common and thought to be important in the generation of their extant diversity. We investigate reticulate evolution in a complex of western North American quillworts (Isoëtes) and provide insights into the evolutionary history of hybrids, and the role of polyploidy in maintaining novel diversity.We utilize low copy nuclear markers, whole plastomes, restriction site-associated DNA sequencing, cytology, and reproductive status (fertile or sterile) to investigate the reticulate evolutionary history of western North American Isoëtes.We reconstruct the reticulate evolutionary history and directionality of hybridization events in this complex. The presence of high level polyploids, plus frequent homoploid and interploid hybridization suggests that there are low prezygotic reproductive barriers in this complex, hybridization is common and bidirectional between similar—but not divergent—cytotypes, and that allopolyploidization is important to restore fertility in some hybrid taxa.Our data provide five lines of evidence suggesting that hybridization and polyploidy can occur with frequency in the genus, and these evolutionary processes may be important in shaping extant Isoëtes diversity.

Background and AimsCrassulacean acid metabolism (CAM) is an adaptation to increase water use efficiency in dry environments. Similar biochemical patterns occur in the aquatic lycophyte genus Isoëtes. It has long been assumed and accepted that CAM-like behaviour in these aquatic plants is an adaptation to low daytime carbon levels in aquatic ecosystems, but this has never been directly tested.MethodsTo test this hypothesis, populations of Isoëtes engelmannii and I. tuckermanii were grown in climate-controlled chambers and starved of atmospheric CO2 during the day while pH was measured for 24 h.Key ResultsWe demonstrate that terrestrial plants exposed to low atmospheric CO2 display diel acidity cycles similar to those in both xerophytic CAM plants and submerged Isoëtes.ConclusionsDaytime CO2 starvation induces CAM-like nocturnal acid accumulation in terrestrial Isoëtes, substantiating the hypothesis that carbon starvation is a selective pressure for this physiological behaviour.

Background: Prickly poppies (genus Argemone , Papaveraceae) epitomize well-defended plants. With high prickle densities and exudation of bright yellow latex from glaucous leaves, there are few reports of herbivore damage on these plants. Yet, little ecological work has examined within-plant or among-species variation in levels of anti-herbivore defenses in prickly poppies. Questions: Are prickly poppies well defended against generalist herbivores? Does chemical defense vary within prickly poppy plants in a pattern consistent with optimal defense theory? Species study: Argemone glauca, A. mexicana , A. ochroleuca, A. platyceras were examined in bioassays using generalist caterpillars, Agrotis ipsilon Hufnagel and Chrysodeixis eriosoma Doubleday (Noctuidae). Study sites and dates: Seeds were collected from field populations in Mexico (2015) and Hawaii (2011); experiment was conducted at the University of Hawaii at Manoa, Fall 2015. Methods: Using a pair of no-choice bioassays, variation in the quality of whole-leaf and chemical extract infused artificial diets for caterpillar development was assessed. Results: Survivorship was lowest on the control lettuce diet, and varied little between poppy diets although pupal mass was marginally lower for caterpillars reared on A. platyceras than A. ochroleuca . Isolating the effects of plant chemistry, C. eriosoma performance was most strongly reduced by seed extracts, with an extension in pupal development time by one week compared to herbivores reared on other diets, as well as a significant reduction in mean adult mass. Conclusions: These results are consistent with optimal defense theory, reflecting greater allocation of defense in tissues of high fitness value ( i.e., seeds). Future work with native herbivores, chemical analyses, and investigations into alternative functions for these plant traits would shed new light on this interesting group of plants.

Background Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. Patients and methods We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. Results A total of 19 RCTs were included in the meta-analysis (n = 62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07–1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85–1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45–0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77–1.07). Conclusions The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Background and AimsCrassulacean Acid Metabolism (CAM) is an adaptation to increase water use efficiency in dry environments. Oddly, similar biochemical patterns occur in the submerged aquatic lycophyte genus Isoëtes. It has long been assumed that CAM-like nocturnal carbon accumulation in aquatic plants is an adaptation to low daytime carbon levels in aquatic ecosystems, but this has never been directly tested.MethodsTo test this hypothesis, populations of terrestrial Isoëtes engelmannii and I. tuckermanii were grown in climate-controlled chambers and starved of atmospheric CO2 during the day while pH was measured for 24-hours.Key resultsWe demonstrate that terrestrial plants exposed to low atmospheric CO2 display diel acidity cycles similar to those in both xerophytic CAM plants and submerged Isoëtes.ConclusionsCO2 starvation induces CAM-like nocturnal carbon accumulation in terrestrial Isoëtes, substantiating the hypothesis that carbon starvation is a selective pressure for nocturnal carbon accumulation in Isoëtes. Furthermore, while aquatic carbon levels undoubtedly promote nocturnal carbon accumulation in extant Isoëtes, the induction of this behavior in terrestrial plants suggests a possible earlier terrestrial evolution of this metabolism in Isoetalean ancestors in response to low atmospheric CO2 levels. We both provide support for a long-standing assumption about nocturnal carbon accumulation Isoëtes as well as suggest an earlier evolution of this behavior.

The vascular architecture of the stem–the stele–is one of the most well studied topics in pteridology, and has fascinated botanists for more than 200 years. Stelar architecture has attracted much attention, in part, due to its diversity in the fern lineage as well as its use as a stable taxonomic character for circumscribing species, genera, families, or larger informal clades. One aspect of stelar morphology that has garnered specific attention is polystely: the development of multiple concentric cylinders of vasculature. This feature has evolved in lineages throughout the fern phylogeny, including in the genus Pteris L. (Pteridaceae). Here, I describe a polycyclic solenostele as a new synapomorphy for Pteris sect. Litobrochia. The identification of this character as a synapomorphy furthers our understanding of the morphological evolution and circumscription of Pteris as well as aides in species identification within this speciose genus.

Women have long been underrepresented in STEM, although there are certain fields within this umbrella that show less of a disparity — the biological sciences being one example. Within biology, pteridology has a rich history of female contributors involved since its inception. In this review we strive to highlight some of the foremost female pteridologists including Elizabeth Knight Britton, Alma Stokey, Irene Manton, Alice Tryon, Barbara Hoshizaki, and Florence Wagner. This is not an exhaustive list, but rather an insight into the strong maternal lineage of the fern and lycophyte community. While the field would not be the same without the work of many male pteridologists, herein we emphasize the important contributions that these founding women have made. Some of the research conducted by early female pteridologists was largely undermined by their time and circumstance; here we bring their lives and works to the foreground. Furthermore, we hope this paper inspires young botanists to enter our unique and historically rich field.

Suite a la demande de la Direction Generale de la Sante, une etude a ete mise en place afin d’evaluer les modalites d’utilisation de l’insuline glargine chez des patients diabetiques en conditions de pratique reelle en France, de decrire le niveau de controle glycemique obtenu et l’incidence des hypoglycemies observees. Il s’agissait d’une etude prospective, observationnelle, multicentrique, nationale de suivi sur un an d’une cohorte de patients diabetiques de type 1 (DT1) et de type 2 (DT2) traites depuis au moins un mois avec de l’insuline glargine et suivis pendant un an par des medecins generalistes, diabetologues et pediatres. L’analyse porte sur 1 707 patients, dont 609 patients DT1 et 1 097 patients DT2 (et un patient avec un diabete non determine). L’âge moyen des patients etait de 42,0 ± 19,4 ans pour les DT1 et de 67,0 ± 11,9 ans pour les DT2, 642 (58,5 %) patients etaient âges de 65 ans et plus et 325 (29,6 %) de 75 ans et plus. L’anciennete moyenne du diabete etait respectivement de 15,8 ± 12,5 et 14,0 ± 8,8 ans. Parmi les patients DT2, 57 % etaient naifs d’insuline avant l’initiation de l’insuline glargine (DT2-IN) et 43 % etaient deja traites par une insuline (DT2-IT). La raison de l’initiation de l’insuline glargine etait principalement un mauvais controle de la glycemie. L’utilisation de l’insuline glargine a conduit a une augmentation importante de l’utilisation du schema therapeutique basal-bolus chez les DT1 et DT2-IT, respectivement de 32 % a 84,7 % et de 8,4 % a 38,8 % et a une diminution du nombre d’antidiabetiques oraux associes chez les DT2-IN, ainsi que chez les patients âges de plus de 65 ans. La dose moyenne d’insuline glargine a l’inclusion etait de 24,2 U/j chez les DT1, de 31,6 U/j chez les DT2-IT et de 23,6 U/j chez les DT2-IN. Au cours du suivi, cette dose est restee stable pour les DT1, et a augmente chez les DT2 (atteignant 35 U/j pour les DT2-IT et 29,7 U/j pour les DT2-IN) La proportion de patients atteignant les objectifs glycemiques (HbA1c En conclusion, les resultats de cette etude en vie reelle ont montre un profil d’utilisation de l’insuline glargine en France conforme au bon usage et aux recommandations de prise en charge du patient diabetique conjointes de la HAS et de l’AFSSAPS en vigueur. Le controle glycemique, initialement ameliore suite a l’instauration de l’insuline glargine, s’est maintenu pendant le suivi a 12 mois. Une augmentation du nombre de patients atteignant l’objectif d’HbA1c (

Chronic obstructive pulmonary disease (COPD), a disease that encompasses emphysema, chronic obstructive bronchitis and small airway obstruction and that is characterised by largely irreversible airflow obstruction, now affects around 10% of the population over the age of 40 yrs 1. The sixth commonest global cause of death in 1990, currently fourth in developed countries, it is expected rise to third place globally by 2020 2. This increase is linked to the trends of its foremost risk factor, tobacco consumption during the twentieth century, and will track the worldwide smoking trends of this century. Besides smoking cessation and pulmonary rehabilitation, the treatment of COPD has previously consisted of bronchodilators early in the disease and oxygen in the late stages. However, because of the presence of inflammation in COPD, short courses of systemic corticosteroids have been used for decades in the treatment of exacerbations, often along with antibiotics. Their side-effects, however, made them unsuitable for the long-term treatment of stable COPD. In the early 1980s, inhaled formulations of corticosteroids were shown to be highly effective for the treatment of asthma and were readily adopted in COPD with no scientific evidence of their benefit in this indication. This transition from asthma to COPD was so natural to prescribers that a Canadian survey conducted in 1994 found that one-third of patients admitted to hospital for COPD were already using inhaled corticosteroids (ICS) 3, despite the fact that no randomised controlled trials had evaluated their effectiveness in COPD. Today, market research studies estimate that the use of these drugs has increased to the point that they are used by >70% of patients with COPD in the USA and Europe, and are currently given as initial therapy to >50% of patients newly diagnosed with COPD, mostly in combination with a long-acting β-agonist (LABA) 4 …

The safety of long-acting beta(2)-agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or all-cause mortality and morbidity were increased with formoterol use. The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol. There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterol-randomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (>90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 microg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABA-treated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant. There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting beta(2)-agonist-randomised patients. However, despite data on >68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

A large number of observational studies, supported by animal and basic research studies, have shown a protective effect of hormone replacement therapy (HRT) on acute coronary outcomes. The recent large randomized Women's Health Initiative (WHI) study reported the opposite result, i.e. a small risk increase of 29% for acute coronary outcomes under estrogen-progestin treatment. Possible methodological reasons for these discrepancies are discussed. Despite randomization, the reported small increase in risk in the WHI study could be spurious because of differential unblinding of HRT users, which could have resulted in higher detection rates of otherwise clinically unrecognized acute myocardial infarction in these women. We show that altering diagnostic patterns because of unblinding could lower the crude rate ratio of 1.28 to 1.02. In the observational studies, the protective effect may have been exaggerated due to a healthy user bias and to the inappropriate choice of the reference group. Using an alternative reference group, the combined rate ratio of 0.67 was increased to 0.82. The diametrical effects of HRT on acute coronary outcomes found between the observational studies and the WHI Study may be a result not only of bias in the observational studies, but also of bias in the WHI Study.

Objective The Protectaid® sponge (Gefar Pharma, Switzerland) is a new feminine barrier contraceptive method containing three low-dose spermicidal agents. In order to evaluate its efficacy and safety profiles, an international, multicenter study has been conducted in four countries. Methods Healthy, presumably fertile and sexually active women were enrolled in this study and were followed at 15 days, 3, 6, 9 and 12 months. Contraceptive efficacy was assessed by a pregnancy test, while safety was evaluated by performing gynecological examinations as well as reporting adverse events. The 'acceptability' of the sponge by the women was assessed through a standard questionnaire. Results A total of 129 women were enrolled in the study, generating 1182 cycles of use of the sponge. The overall efficacy rate was 77%, with no significant influence of age or parity. Acceptability was high, with 85% of subjects being symptom- or problem-free while using the sponge. Finally, the safety profile was very good, with no cl...

Resume Les effets secondaires des drogues sont rapportes par des case reports ou par des etudes randomisees pour un autre objectif. Comportant souvent de nombreux biais, des etudes observationnelles sont cependant necessaires pour evaluer et quantifier les risques, de meme que la creation de databases qui permettent ces etudes.

The decline in lung function over time is a fundamental measure of disease progression among patients with chronic obstructive pulmonary disease (COPD). As a result, forced expiratory volume in one second (FEV1) decline has been used as a central outcome measure for many randomised controlled trials evaluating whether pharmacological treatments could modify the natural history of COPD. These trials, mostly focussed on assessing the benefit of inhaled corticosteroids, and their meta-analyses highlighted the complexities of analysing data from repeated FEV1 measurements over time, particularly in the context of studying COPD patients who discontinue follow-up early and in large numbers. This has lead to contradictory results and divergent conclusions 1–3. At present, the recent paper from the Towards a Revolution in COPD Health (TORCH) trial reports that the yearly decline in FEV1 was significantly slower with fluticasone, salmeterol or both compared with placebo 4. A common misconception in the interpretation of these studies is that the effect of the study drug on FEV1 decline is likely to be greater than the data suggest. The rationale is that more patients receiving placebo were discontinuing the study drugs and the patients who dropped out early had a steeper decline in lung function than those who remained. Consequently, it has generally been believed that the resulting analysis “actually minimises the differences observed in the rate of FEV1 decline” 4. To clarify this misconception, a fundamental aspect of the design and statistical analysis of these trials is addressed, namely bias from regression to the mean resulting from the absence of an authentic intent-to-treat approach. It is described based on the TORCH trial and illustrated using data from the Canadian Optimal randomised trial. Most of the trials to date are not designed for a full intent-to-treat …

Les grandes bases de donnees informatisees de sante sont maintenant utilisees regulierement en pharmaco-epidemiologie afin d’etudier les risques et benefices de nombreux medicaments. Cette utilisation a eu un essor prodigieux ces dernieres annees a travers le monde ou ces bases sont souvent ouvertement accessibles. Plusieurs etudes basees sur une approche cohorte ont donne lieu a des resultats inattendus proferant des benefices prodigieux a certains medicaments. Nous presenterons des exemples d’etudes sur les effets des statines et des steroides inhales sur la mortalite, et plus recemment les effets de la metformine sur l’incidence du cancer, demontrant que leurs effets surprenants sont dus directement a plusieurs biais relies au temps. Ceux-ci incluent le biais du au temps immortel et au temps immesurable, resultant d’une analyse inappropriee des donnees ou directement d’un resultat de la nature des bases de donnees, qui seront decrits. Un deuxieme defi est relie a la taille de ces bases qui peuvent generer des cohortes gigantesques. La taille de la cohorte, le nombre eleve de cas de l’evenement indesirable etudie, ainsi que l’exposition au medicament qui varie souvent dans le temps, tout comme plusieurs facteurs confondants, font qu’une analyse integrale de la cohorte est generalement irrealisable. L’approche cas-temoin niche dans la cohorte est frequemment utilisee et tres efficace dans de telles situations. Cette approche est cependant mal comprise hors de la communaute epidemiologique et statistique, comme par exemple dans le milieu medical general et specialise qui est plus a l’aise avec l’approche cohorte directe. L’approche quasi-cohorte a ete proposee specifiquement pour parer a cela. Celle-ci est tout comme une etude cas-temoin nichee dans la cohorte, amis qui presente les donnees comme une cohorte et qui permet, en plus de l’estimation du risque relatif, celle du risque absolu et de l’exces de risque (difference des taux). Nous presenterons l’exemple d’une etude quasi-cohorte sur le risque de pneumonie associe a l’utilisation des steroides inhales en maladie pulmonaire obstructive chronique (MPOC). Enfin, meme avec de grandes bases de donnees, plusieurs initiatives individuelles sont souvent insuffisantes pour etudier les evenements indesirables rares mais serieux, les medicaments utilises pour des maladies rares, des effets modestes, et les effets des medicaments peu apres leur mise sur le marche lorsque leur utilisation n’est pas encore repandue. Pour repondre a ces limitations en raison de donnees insuffisantes, plusieurs initiatives impliquant la mise en commun de plusieurs bases de donnees ont ete introduites dans le monde entier. Nous presenterons l’exemple du reseau pancanadien CNODES (« Canadian Network for Observational Drug Effect Studies ») forme specifiquement pour relever le defi de l’insuffisance de donnees dans l’evaluation de l’innocuite des medicaments. L’utilisation simultanee de plusieurs bases de donnees provinciales et internationales pose des defis methodologiques specifiques au design et a l’analyse statistiques dans ces etudes. Nous discuterons de plusieurs exemples recents d’etudes de l’innocuite des statines et des nouveaux medicaments antidiabetiques.

Background Patients with RA may be at an increased risk for malignancies compared with the general population, and treatment with TNF inhibitors have been reported to further increase this risk. 1 Abatacept, the first selective co-stimulation modulator for the treatment of RA, has a mechanism of action that is fundamentally different from that of other biologic agents. Objectives This cohort study aimed to compare the risk of malignancy between patients initiating abatacept and patients initiating other biologic treatments. Methods Adult patients diagnosed with RA in the MarketScan® Commercial and Supplemental Medicare database who initiated treatment with abatacept or another biologic treatment between 1 July 2006 and 30 September 2014 were eligible for inclusion in the analysis. Patients were required to have at least 180 days of continuous health plan enrolment prior to, and ≥1 day following, initiation of the qualifying RA treatment. Patients were presumed to have initiated a treatment if there was no claim for that particular drug in the 180 days prior to the index date. Therefore, patients initiating abatacept or another biologic treatment may be initiating a biologic for the first time or switching from one biologic to another. Malignancies were identified by International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Patients were followed from 180 days after the date of initiation of abatacept or another biologic treatment until occurrence of a malignancy (identified by ICD-9 code), end of enrolment in the database or end of data collection, whichever occurred first. Patients who had an ICD-9 code for a malignancy in the 6 months prior to or after the date of initiation were excluded. Crude incidence rates were calculated for each cohort. After matching each initiator of abatacept with 1 or 2 initiators of other biologic treatments on the propensity score, a Cox regression analysis was performed to estimate the hazard ratio. Results A total of 17,670 patients initiating abatacept and 50,641 initiating another biologic were identified. During an average follow-up of 1.4 years for abatacept initiators and 1.6 years for other biologic initiators, there were 1132 and 2933 patients with an incident event of malignancy, respectively. This resulted in incidence rates of 44 (95% CI: 42, 47) and 36 (35, 38) per 1000 person-years in abatacept initiators and other biologic initiators, respectively. The propensity score analysis resulted in 17,517 patients initiating abatacept matched with 32,277 patients initiating another biologic. After adjusting for prior biologic treatment, the hazard ratio of malignancy with abatacept relative to other biologic agents was 1.10 (0.98, 1.23). Hazard ratios for lung cancer, lymphoma, breast cancer and non-melanoma skin cancer were also similar between the two. Conclusions In this large, real-world study of patients treated for RA, the risk of malignancy was not significantly different for those who initiated abatacept compared with those who initiated other biologic agents. References Mercer LK, et al. Ann Rheum Dis 2015;74:1087–93. Disclosure of Interest S. Suissa Consultant for: Bristol-Myers Squibb, Genentech, Roche, N. Baker Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, H. Kawabata Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, N. Ray: None declared, T. Simon Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Clinical trials usually use the relative risk (rate ratio or hazard ratio) to compare the effects of one treatment modality with others. However, the numbers needed to treat/harm (NNT/NNH) are sometimes used as another way of presenting an estimate of the effect of a medical intervention, pointing at the number of patients needed to be exposed over a certain period of time in order to achieve one beneficial or adverse event. For clinicians and patients, this is a very simple and clear tool to demonstrate the consequences of a specific intervention. Epidemiologists and statisticians are more cautious with interpretations of data of that sort. This article brings the relevant perspectives of a clinician, an epidemiologist and a statistician in regard to the value of NNT/NNH.

The authors conducted a population-based case-control study to investigate whether clinically observed chickenpox, linked with a level of intensity for clinical expression, increases the risk of multiple sclerosis (MS) in childhood. The cases were MS patients whose disease onset occurred between 1994 and 2003, before age 16 years, in France. Each case was matched for age, sex, and geographic origin with as many as 12 controls randomly selected from the general population. Information about clinically observed chickenpox in cases and controls before the index date regarding onset of MS was collected with a standardized questionnaire and was checked against health certificates. Conditional logistic regression was used to estimate the odds ratio for an association between MS and chickenpox. The 137 MS cases were matched with 1,061 controls. Clinically observed chickenpox had occurred in 76.6% of the cases and 84.9% of their matched controls. The adjusted odds ratio of MS onset associated with chickenpox occurrence was 0.58 (95% confidence interval: 0.36, 0.92). The authors concluded that clinically observed chickenpox was associated with a lower risk of childhood-onset MS in a French population.

Background In the absence of randomized controlled trials to support therapeutic decisions in pediatric MS (multiple sclerosis), comparative observational studies based on the real practice of physicians are important tools. Aim To assess the effectiveness of beta interferon (sIFN) in preventing the first attack and severe disability after confirmed MS diagnosis in a pediatric cohort. Methods A cohort of 197 relapsing-remitting pediatric MS patients was studied (1990-2005). Patients were followed from MS diagnosis until the first subsequent attack or severe disability occurrence ( DSS score of ⩾4) or were censored. The Cox model, with time-dependent sIFN exposure to account for the varying times of starting this treatment, was used to estimate the effect of sIFN on the risk of this attack or severe disability , adjusting for potential confounding factors. Results During cohort follow-up (mean 5.5 years), 70.5% of the 197 children had a first attack (80% within the first 2 years) and 24 started sIFN (mean delay 3.6 months; mean duration 17.1 months). The use of sIFN was associated with a significant reduction in the rate of the first attack during the first year of treatment (hazard ratio: 0.31, 95% confidence interval: 0.13–0.72) as well as the first 2 years (0.40, 0.20–0.83). This effect was less significant over the entire follow-up of up to 4 years of treatment (0.57, 0.30–1.10). The use of sIFN suggests a reduction on the occurrence of severe disability , although not statistically significant ( HR 0.78; 95% CI : 0.25–2.42). Conclusions The use of sIFN, given after the diagnosis of MS, significantly reduces the risk of relapse during the first 2 years.

A large number of observational studies, supported by animal and basic research studies, have shown a protective effect of hormone replacement therapy (HRT) on acute coronary outcomes. The recent large randomized Women's Health Initiative (WHI) study reported the opposite result, i.e. a small risk increase of 29% for acute coronary outcomes under estrogen-progestin treatment. Possible methodological reasons for these discrepancies are discussed. Despite randomization, the reported small increase in risk in the WHI study could be spurious because of differential unblinding of HRT users, which could have resulted in higher detection rates of otherwise clinically unrecognized acute myocardial infarction in these women. We show that altering diagnostic patterns because of unblinding could lower the crude rate ratio of 1.28 to 1.02. In the observational studies, the protective effect may have been exaggerated due to a healthy user bias and to the inappropriate choice of the reference group. Using an alternative reference group, the combined rate ratio of 0.67 was increased to 0.82. The diametrical effects of HRT on acute coronary outcomes found between the observational studies and the WHI Study may be a result not only of bias in the observational studies, but also of bias in the WHI Study.

Asthma treatment guidelines were introduced in Japan in the 1990s, insisting as elsewhere, on the importance of anti-inflammatory therapy. The present study assessed whether use of anti-inflammatory medications was associated with a decrease in asthma mortality in Japan, the first country to use leukotriene receptor antagonists. A population-based ecological study was conducted, spanning the period 1987-1999, among people aged 5-34 yrs in Japan. The association between the yearly rate of asthma death and sales of inhaled corticosteroids and leukotriene receptor antagonists was estimated using Poisson regression. The yearly asthma death rate was stable at 6-7 deaths per million before the introduction of leukotriene receptor antagonists in 1995 and decreased by 23% thereafter, reaching 3.5 per million in 1999. The rate of asthma death was found to decrease with increasing use of both leukotriene receptor antagonists and inhaled corticosteroids. The rate ratio of asthma death was 0.96 per 1 million 25-day treatment courses of inhaled corticosteroids and 0.80 for every 1 million 25-day treatment courses of leukotriene receptor antagonists, consumed per year in Japan. The increasing use of inhaled corticosteroids and leukotriene receptor antagonists may have contributed to the significant reduction in asthma mortality among young asthmatics in Japan.

The role of psychological factors in recovery from first lifetime low back pain (LBP) was explored in this study. Consecutive clients from one physiatry clinic in Montreal who had LBP of less than 3 months' duration, were on sick leave and receiving workers' compensation benefits, and reported the current event as first lifetime LBP were enrolled. Psychological factors that fluctuate with current events (Psychiatric Symptom Index) and remain stable over time (General Well Being Scale) were assessed. Outcomes were late return to work (31 days) and 1 year incidence of compensated recurrence. Results from two multivariate models indicated lower psychological distress predicted late return to work, and higher well being, higher aggressiveness, and lower anxiety predicted compensated recurrence. Researchers concluded psychological factors do not impact clients with all types of LBP in the same way. For individuals lacking prior LBP experience, better psychological functioning increased lengthy work absence. Thus, awareness of the clients' psychological profiles and previous LBP experiences may benefit recovery.

The Protectaid sponge (Gefar Pharma, Switzerland) is a new feminine barrier contraceptive method containing three low-dose spermicidal agents. In order to evaluate its efficacy and safety profiles, an international, multicenter study has been conducted in four countries.Healthy, presumably fertile and sexually active women were enrolled in this study and were followed at 15 days, 3, 6, 9 and 12 months. Contraceptive efficacy was assessed by a pregnancy test, while safety was evaluated by performing gynecological examinations as well as reporting adverse events. The 'acceptability' of the sponge by the women was assessed through a standard questionnaire.A total of 129 women were enrolled in the study, generating 1182 cycles of use of the sponge. The overall efficacy rate was 77%, with no significant influence of age or parity. Acceptability was high, with 85% of subjects being symptom- or problem-free while using the sponge. Finally, the safety profile was very good, with no clinically significant evidence of local or systemic adverse reactions.The new Protectaid sponge is a safe and effective non-hormonal contraceptive method for women.

There has been some concern that vaccination may precipitate the onset of multiple sclerosis or lead to relapses. Since the recent hepatitis B vaccination program in France, there have been new reports of an increased risk of active multiple sclerosis after vaccination.We conducted a case-crossover study to assess whether vaccinations increase the risk of relapse in multiple sclerosis. The subjects were patients included in the European Database for Multiple Sclerosis who had a relapse between 1993 and 1997. The index relapse was the first relapse confirmed by a visit to a neurologist and preceded by a relapse-free period of at least 12 months. Information on vaccinations was obtained in a standardized telephone interview and confirmed by means of medical records. Exposure to vaccination in the two-month risk period immediately preceding the relapse was compared with that in the four previous two-month control periods for the calculation of relative risks, which were estimated with the use of conditional logistic regression.Of 643 patients with relapses of multiple sclerosis, 15 percent reported having been vaccinated during the preceding 12 months. The reports of 94 percent of these vaccinations were confirmed. Of all the patients, 2.3 percent had been vaccinated during the preceding two-month risk period as compared with 2.8 to 4.0 percent who were vaccinated during one or more of the four control periods. The relative risk of relapse associated with exposure to any vaccination during the previous two months was 0.71 (95 percent confidence interval, 0.40 to 1.26). There was no increase in the specific risk of relapse associated with tetanus, hepatitis B, or influenza vaccination (range of relative risks, 0.22 to 1.08). Analyses based on risk periods of one and three months yielded similar results.Vaccination does not appear to increase the short-term risk of relapse in multiple sclerosis.

The debate on the association between nonphenacetin-containing combined analgesics and renal disease has lasted for several years.A peer review committee of scientists, selected jointly by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry was asked to critically review data on the relationship between nonphenacetin combined analgesics and nephropathy.The committee regarded epidemiologic evidence on nonphenacetin combined analgesics as inconclusive because of sparse information and substantial methodological problems. The committee also noted that a diagnosis of analgesic-associated nephropathy (AAN) in clinical practice usually depends on information about exposure before or in the early stages of the disease and is seldom accompanied by specific histologic evidence. The morphologic finding of papillary calcification can arise from other conditions and is not specific for AAN. For these reasons, the identification criteria for AAN should be reappraised with scientific methods to validate the diagnostic procedure. In the limited amount of experimental pharmacological data in humans and animals, the committee found no convincing evidence to confirm or refute the hypothesis that nonphenacetin combined analgesics are more nephrotoxic than single formulations. For caffeine taken with combined analgesics, the currently available information is not sufficient to postulate a harmful toxicological effect.The committee's two main conclusions were that sufficient evidence is absent to associate nonphenacetin combined analgesics with nephropathy and that new studies should be done to provide appropriate data for resolving the question.

To determine whether the pain, contracture, and disability associated with idiopathic frozen shoulder are diminished by a series of 3 indirect bupivacaine suprascapular nerve blocks delivered in an ambulatory care clinic.A double blind randomized controlled trial of patients referred by primary care and specialty clinics in Montreal to an ambulatory tertiary care academic facility. Patients and controls underwent a series of 3 indirect suprascapular nerve blocks at 7 day intervals using either 10 c.c. bupivacaine 0.5 (Marcaine) in the treatment group or 10 c.c. of physiological saline in controls. Subjects in both groups were taught a program of shoulder range of motion exercises to be done at home. The primary outcome measure was the McGill-Melzack Pain Questionnaire (MPQ) short form at 1 month post-randomization (2 weeks after last injection). The secondary outcome measures were disability measured by the simple shoulder test and glenohumeral joint contracture measured by shoulder range of motion measurements.Thirty-four subjects were randomized from 58 screened. Average age of subjects was 52 years. Mean duration of pain prior to randomization was one year. Dropout rate was 11% in the treatment group, 30% in the placebo group. A 64% reduction in pain in the treatment group versus 13% in the placebo group was observed at one month as measured by the MPQ multidimensional pain descriptors score (p = 0.03). A nonsignificant 15.8% improvement in shoulder function in the treatment group versus 4% in the placebo group (p = 0.24) was also noted. No improvement in shoulder range of movement was noted. No side effects other than transient vagal symptoms and local tenderness at the injection site were reported.The use of bupivacaine suprascapular nerve blocks was effective in reducing the pain of frozen shoulder at one month. Clinical studies with a larger number of subjects and a longer study period will help determine the duration and nature of the effect of bupivacaine suprascapular nerve blocks in treating the pain, disability, and glenohumeral joint contracture of frozen shoulder.

BACKGROUND: Reference-based pricing is a cost-containment policy applied to prescription drugs that are in the same class and deemed to be therapeutically equivalent. Recent reference-based pricing measures have targeted several drug classes, including angiotensin-converting-enzyme (ACE) inhibitors. The objective of this study was to assess whether patients treated for hypertension with various ACE inhibitors differed in their utilization of health care services and hence, whether the various ACE inhibitors should be considered therapeutically equivalent. METHODS: A retrospective cohort was formed from 4709 Saskatchewan residents aged 40-79 years who initiated treatment for hypertension with 1 of the 3 most frequently prescribed ACE inhibitors (captopril, enalapril or lisinopril) between Jan. 1, 1991, and Dec. 31, 1993. Information obtained from universal insurance databases included prescription drug use, the number of visits to a general practitioner (GP) or specialist and the number of hospital admissions during the year before treatment was initiated and during a follow-up period of up to 4 years. Rates were statistically adjusted for potential confounding variables and compared across treatment groups. RESULTS: Of the 4709 patients, 529 were prescribed captopril initially, 2939 enalapril and 1241 lisinopril. After treatment was initiated patients prescribed captopril were dispensed more medications on average, with an overall rate of 18.6 prescriptions per patient per year (v. 16.4 and 14.7 for enalapril and lisinopril users respectively); they were admitted to hospital more often, and they made more visits to GPs and specialists. The adjusted rate ratio of the number of visits to a GP for patients receiving enalapril, relative to captopril, was 0.84 (95% confidence interval [CI] 0.80-0.88), and for those receiving lisinopril it was 0.79 (95% CI 0.74-0.83). The adjusted rate ratios for the number of visits to a specialist were similar but lower, and for the number of hospital admissions they were 0.82 for patients prescribed enalapril initially (95% CI 0.73-0.93) and 0.65 (95% CI 0.56-0.75) for those prescribed lisinopril. INTERPRETATION: Patients with hypertension who are initially prescribed captopril used health care services more than those initially prescribed enalapril or lisinopril. This suggests that ACE inhibitors may not be therapeutically equivalent.

To the Editors: The recent paper by Keene et al. 1 that reviews different approaches for the analysis of exacerbation rates is valuable because of the central role of exacerbations in evaluating the benefits of drugs in chronic obstructive pulmonary disease (COPD) trials 1. The authors present reanalyses of the TRISTAN (Trial of Inhaled Steroids and Long-acting β2-agonists) and ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) trial data, which have been previously identified as incorrectly analysed because of the absence of consideration for between-subject variability in exacerbation rates 2. With the proper reanalyses, their conclusions from these trials remain the same; namely that inhaled corticosteroids (ICSs) with or without long-acting β-agonists reduce the frequency of …

PREMESSE: Case reports e studi ecocardiografici suggeriscono che i dopamino agonisti derivati dell’ergot pergolide e cabergolina possono aumentare il rischio di insufficienza valvolare cardiaca. METODI: Per questo studio sono stati utilizzati dati dell’United Kingdom General Practice Database per identificare una coorte di 11417 soggetti tra i 40 e gli 80 anni, ai quali erano stati prescritti farmaci dopamino agonisti nel periodo tra il I gennaio 1988 ed il 31 agosto 2005. Ogni paziente con nuova diagnosi (clinica e strumentale) di insufficienza valvolare cardiaca e stato messo a confronto con soggetti di controllo (fino a 25 soggetti per ogni paziente), in accordo con eta, sesso, ed anno di ingresso nella coorte. L’incidenza di insufficienza valvolare con diversi dopamino-agonisti e stata stimata mediante analisi di regressione logistica condizionale. RISULTATI: Nella coorte sono stati identificati 31 pazienti con nuova diagnosi di insufficienza valvolare (piu frequentemente insufficienza mitralica). Di questi, 6 erano ancora trattati con pergolide (al 31 agosto 2005), 6 con cabergolina, mentre 19 avevano sospeso il trattamento con dopamino-agonisti da almeno un anno. L’analisi statistica ha dimostrato che il rischio di sviluppare insufficienza valvolare era aumentato nei soggetti in trattamento con pergolide (rischio relativo 7.1; 95% intervallo di confidenza, 2.3–22.3), o cabergolina (rischio relativo 4.9; 95% intervallo di confidenza, 1.5–15.6), ma non nei soggetti in trattamento con altri dopamino-agonisti. CONCLUSIONI: In questo studio l’uso dei dopamino agonisti pergolide e cabergolina risulta associato con un aumentato rischio di sviluppare insufficienza valvolare cardiaca.

Calcium channel blockers have been reported to increase the risk of gastrointestinal bleeding. We tested this hypothesis, and also assessed whether beta blockers decrease this risk.A nested case-control design within a population-based cohort of all 34,074 new users of beta blockers, angiotensin-converting enzyme (ACE) inhibitors, or calcium channel blockers in Saskatchewan, from 1990 to 1993 and followed up to March 1995, was used. We identified all 311 subjects hospitalized because of gastrointestinal bleeding during this period, each of whom was matched to 10 randomly selected controls.The rate of hospitalization for gastrointestinal bleeding was 3.0 per 1,000 per year. The adjusted rate ratio of gastrointestinal bleeding for current use of calcium channel blockers was 1.1 (95% confidence interval [CI] 0.8 to 1.4) and 0.66 (95% CI 0.44 to 0.98) for beta blockers compared with no current use of anti-hypertensive drugs. The adjusted rate ratio for ACE inhibitor use was 1.0 (95% CI 0.7 to 1.3) while that for diuretic use was 1.4 (95% CI 1.0 to 2.0).The use of calcium channel blockers does not appear to increase the risk of gastrointestinal bleeding in the first five years of treatment, while beta blockers may prevent this adverse event. The unexpected elevated risk associated with the use of diuretics needs to be investigated further.