Isotopic niche size of Coregonus artedi (sensu lato) Increases in the presence of Mysis diluviana, expanded habitat use and phenotypic diversity.

Post-glacial colonization of lakes in Algonquin Park, Ontario, Canada resulted in food webs with cisco (Coregonus artedi sensu lato) and either Mysis diluviana or Chaoborus spp. as the dominant diel migrator. Mysis as prey, its diel movements and benthic occupancy, are hypothesized to be key elements of ecological opportunity for cisco diversity in the Laurentian Great Lakes. If correct, the hypothesis strongly implies that lakes with Mysis would have greater trophic niche size and drive greater adaptive radiation of cisco forms relative to lakes without Mysis. The dichotomy in diel migrator in Algonquin Park lakes was an opportunity to assess the isotopic niche size of cisco (δ15N and δ13C) and determine if niche size expands with Mysis presence. We found the presence of Mysis is necessary to expand isotopic niche size in our study lakes. The use of habitats not typically associated with the ancestral form of cisco (e.g., benthic habitats) and phenotypic diversity (blackfin and cisco) also continue to expand niche size in Mysis-based food webs. Partial ecological speciation based on a large niche space appears to be present in one lake (Cauchon Lake) where use of alternative habitats is the only real difference in cisco. The presence of blackfin expands niche space in Cedar and Radiant Lakes. This was not matched in Hogan Lake where niche space was relatively smaller with similar forms. Possible reasons for this discrepancy may be related to the asymmetric basin of Hogan Lake and whether the two forms overlap during cool and cold-water periods of the annual temperature cycle. By comparing trophic niche size among lakes with and without Mysis, we conclude that Mysis provides a key ecological opportunity for cisco diversity in our study lakes and likely more widely.

Evolution and diversity of two cisco forms in an outlet of glacial Lake Algonquin.

The diversity of Laurentian Great Lakes ciscoes (Coregonus artedi, sensu lato) arose via repeated local adaptive divergence including deepwater ciscoes that are now extirpated or threatened. The nigripinnis form, or Blackfin Cisco, is extirpated from the Great Lakes and remains only in Lake Nipigon. Putative nigripinnis populations were recently discovered in sympatry with artedi in a historical drainage system of glacial Lake Algonquin, the precursor of lakes Michigan and Huron. Given the apparent convergence on Great Lakes form, we labeled this form blackfin. Here, we test the hypothesis that nigripinnis may have colonized this area from the Great Lakes as a distinct lineage. It would then represent a relict occurrence of the historical diversity of Great Lakes ciscoes. Alternatively, blackfin could have evolved in situ in several lakes. We captured more than 600 individuals in the benthic or pelagic habitat in 14 lakes in or near Algonquin Provincial Park (Ontario, Canada). Fish were compared based on habitat, morphology, and genetic variation at 6,676 SNPs. Contrary to our expectations, both cisco and blackfin belonged to an Atlantic lineage that colonized the area from the east, not from the Great Lakes. Sympatric cisco and blackfin were closely related while fish from different lakes were genetically differentiated, strongly suggesting the repeated in situ origin of each form. Across lakes, there was a continuum of ecological, morphological, and genetic differentiation that could be associated with alternative resources and lake characteristics. This study uncovers a new component of cisco diversity in inland lakes of Canada that evolved independently from ciscoes of the Laurentian Great lakes. The diversity of cisco revealed in this study and across their Canadian range presents a challenge for designating conservation units at the intraspecific level within the framework of the Committee on the Status of Endangered Wildlife in Canada (COSEWIC).

Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension: A Systematic Review.

BACKGROUND: Relative risk (RR) and number needed-to-treat (NNT) are frequently time-dependant measures. We performed a systematic review and meta-analysis to assess whether trial duration influenced the relative and absolute risk of worsening in randomized controlled trials (RCTs) comparing combination therapy (CT) of pulmonary arterial hypertension (PAH)-specific therapies vs monotherapy (MT). METHODS: We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to September 2016) for RCTs assessing CT compared with MT in PAH. The primary outcome was the risk of clinical worsening. We assessed whether trial duration correlated with RR and NNT using weighted meta-regression with mixed effects. Changes in NNT overtime were also assessed using data from long-term event-driven trials. RESULTS: There were 3,801 patients throughout 15 studies included. The RR for clinical worsening positively correlated with trial duration (R2 = 0.67, P = .0002), whereas the NNT did not (mean NNT, 7; R2 = 0.02; P = .65). Among long-term event-driven trials, the mean NNT progressively decreased until 52 weeks of follow-up, being stable thereafter. Conversely, the mean RR progressively increased from approximately 0.40 at week 16 to approximately 0.68 at week 104. CONCLUSIONS: Absolute risk reduction of clinical worsening was relatively constant beyond 6 to 12 months of treatment in clinical trials comparing CT with MT in PAH. These results question the need for CT trials of very long duration in PAH.

Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis.

BACKGROUND: Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model. FINDINGS: Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% [332 of 1940 patients] vs monotherapy 28% [517 of 1862 patients], risk ratio [RR] 0·65 [95% CI 0·58-0·72], p<0·00001). We noted no heterogeneity between the studies (I(2)=18%, phomogeneity=0·25). A publication bias was suggested by the results of an Egger test (t=-2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 [95% CI 0·58-0·73], p<0·00001). INTERPRETATION: In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed. FUNDING: None.