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Hypertension during pregnancy increases the risk of adverse maternal and fetal outcomes, but the mechanisms of pregnancy hypertension are not precisely understood. Elevated plasma renin activity and aldosterone concentrations play an important role in the normal physiologic adaptation to pregnancy. These effectors are reduced in patients with pregnancy hypertension, creating an opportunity to define the features of the renin–angiotensin–aldosterone system (RAAS) that are characteristic of this disorder. In the current study, we used a novel LC-MS/MS-based methodology to develop comprehensive profiles of RAAS peptides and effectors over gestation in a cohort of 74 pregnant women followed prospectively for the development of gestational hypertension and pre-eclampsia (HYP, 27 patients) versus those remaining normotensive (NT, 47 patients). In NT pregnancy, the plasma renin activity surrogate, (PRA-S, calculated from the sum of Angiotensin I + Angiotensin II) and aldosterone concentrations significantly increased from the first to the third trimester, accompanied by a modest increase in the concentrations of angiotensin peptide metabolites. In contrast, in HYP pregnancies, PRA-S and angiotensin peptides were largely unchanged over gestation, and third-trimester aldosterone concentrations were significantly lower compared with those in NT pregnancies. The results indicated that the predominant features of pregnancies that develop HYP are stalled or waning activation of the RAAS in the second half of pregnancy (accompanied by unchanging levels of angiotensin peptides) and the attenuated secretion of aldosterone.

Low recruitment due to limitations of propagule supply or post-settlement survival reinforces dominance of turf algal assemblages that replace canopy algae following large-scale losses. However, post-recruitment processes that hinder juvenile growth and survival (epiphytic overgrowth, grazing, physical stress) also could impede recovery. To evaluate the contribution of recruitment, growth, and survival of young sporophytes to recovery of degraded kelp populations and key factors driving post-recruitment tissue loss and mortality, we followed cohorts of juvenile kelp Saccharina latissima at two defoliated sites in Nova Scotia. We also monitored kelp recruitment, abundance, size structure, and macroalgal composition for 5.5 years. Recruit densities were an order of magnitude lower compared to previous studies in the region. Large decreases in blade area of juveniles were related to cover by the invasive bryozoan Membranipora membranacea, grazing by small snails Lacuna vincta, and warm seawater temperatures. Cohort survival was low (time to 50% mortality 2.5–5.5 months) and increased risk of death was directly related to bryozoan encrustation. Modest seasonal or interannual gains in kelp abundance were lost during periods of peak temperature, which showed a warming trend during the study, favouring persistence of widespread turf-forming, opportunistic and invasive algae. We conclude that low recruitment success, high rate of tissue loss relative to growth, and high mortality, inhibited kelp recovery. Impacts of epiphytic overgrowth, grazing, and warm temperatures on these processes highlight the need to protect intact kelp populations, growing in favourable conditions, to maintain positive interactions that increase resilience to undesirable regime shifts.

Emerging evidence indicates a previously unrecognized, clinically relevant spectrum of abnormal aldosterone secretion associated with hypertension severity. It is not known whether excess aldosterone secretion contributes to hypertension during pregnancy. We quantified aldosterone concentrations and angiotensin peptides in serum (using liquid chromatography with tandem mass spectrometry) in a cohort of 128 pregnant women recruited from a high-risk obstetrics clinic and followed prospectively for the development of gestational hypertension, pre-eclampsia, superimposed pre-eclampsia, chronic hypertension, or remaining normotensive. The cohort was grouped by quartile of aldosterone concentration in serum measured in the first trimester, and blood pressure, angiotensin peptides, and hypertension outcomes compared across the four quartiles. Blood pressures and body mass index were greatest in the top and bottom quartiles, with the top quartile having the highest blood pressure throughout pregnancy. Further stratification of the top quartile based on increasing (13 patients) or decreasing (19 patients) renin activity over gestation revealed that the latter group was characterized by the highest prevalence of chronic hypertension, use of anti-hypertensive agents, pre-term birth, and intrauterine growth restriction. Serum aldosterone concentrations greater than 704 pmol/L, the 75th percentile defined within the cohort, were evident across all categories of hypertension in pregnancy, including normotensive. These findings suggest that aldosterone excess may underlie the development of hypertension in pregnancy in a significant subpopulation of individuals.

Introduction Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act’s Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.e., small molecule vs. biologic). Methods This cross-sectional study evaluated oncology drugs first approved by the FDA from 2008 to 2018 and later approved for one or more additional indications. Numbers, types, and approval timelines of subsequent indications were recorded at the drug level, with drugs grouped by quartile based on the pacing of post-approval development (i.e., “rapid pace” to “measured pace”). Results Multi-indication oncology drugs ( N  = 56/86, 65.1%) had one or more subsequent indication approved in a new: cancer type (60.7%), line of treatment (50.0%), combination (41.1%), mutation (32.1%), or stage (28.6%). The median time between FDA approvals for indications increased from 0.6 years (IQR: 0.48, 0.74) in the “rapid pace” group to 1.6 years (IQR: 1.32, 1.66), 2.4 years (IQR: 2.29, 2.61), and 4.9 years (IQR: 3.43, 6.23) in the “moderate,” “measured-moderate,” and “measured” pace groups, respectively. Drugs in the “rapid pace” group often received their first subsequent indication approval within 9 months of initial approval (median: 0.7 years; IQR: 0.54, 1.59), whereas the “measured pace” group took a median of 5.7 years (IQR: 3.43, 6.98). Across all multi-indication drugs, the median time to the most recent approval for a subsequent indication was 5.5 years (IQR: 3.18, 7.95). One quarter (25%) of drugs were approved for their most recent subsequent indication after the time at which they would be DPNP-eligible. Conclusion Approval histories of new oncology drugs demonstrate the role of post-approval indications in expanding treatment options towards new cancer types, stages, lines, combinations, and mutations. Heterogeneous clinical development pathways provide insights into potential unintended consequences of IRA-related changes surrounding post-approval research and development.

Declines in kelp abundance over the past 3 decades have resulted in a shift from luxuriant kelp beds to extensive mats of turf-forming algae in Nova Scotia, Canada. With the reduced availability of open rocky substrate, kelps are increasingly recruiting to turf algae. At 3 sites near Halifax, we found that turf-attached kelp Saccharina latissima was generally restricted to smaller size classes (< 50 cm length) than rock-attached kelp at 12 m depth. Turf-attached kelp allocated a greater proportion of biomass to the holdfast (anchoring structure), which differed morphologically from that of rockattached kelp and had lower attachment strength. To assess how these differences affect survival, we monitored kelp in 2 m diameter plots at 11 m depth over 40 wk at 1 site. Smaller kelps were predominantly turf-attached and larger ones rock-attached in late summer and autumn, but there was near-complete loss of both turf- and rock-attached kelp over winter when wave action was greatest. In a concurrent manipulative experiment at 5 m depth at another site, we transplanted small boulders with turf- or rock-attached kelp to a wave-exposed or protected location. Survival was greater for rock-attached transplants at both locations after 12 wk, with a complete loss of turf-attached kelp in the wave-exposed treatment. Classification based on holdfast morphology showed that 76% of drift kelp within a depositional area at this site was once turf-attached. Low survival of kelps that recruit to turf algae, likely due to wave dislodgement, may represent an important feedback that increases resilience of a turf-dominated state and prevents reestablishment of kelp.

Baseline data on the distribution and extent of biogenic habitat-forming species at a high spatial resolution are essential to inform habitat management strategies, preserve ecosystem integrity, and achieve effective conservation objectives in the nearshore. Model-based approaches to map suitable habitat for these species are a key tool to address this need, filling in gaps where observations are otherwise unavailable and remote sensing methods are limited by turbid waters or cannot be applied at scale. We developed a high resolution (35 m) ensemble species distribution model to predict the distribution of eelgrass ( Zostera marina ) along the Atlantic coast of Nova Scotia, Canada where the observational coverage of eelgrass occurrence is sparse and nearshore waters are optically complex. Our ensemble model was derived as a performance-weighted average prediction of 7 different modeling methods fit to 6 physical predictors (substrate type, depth, wave exposure, slope, and two bathymetric position indices) and evaluated with a 5-fold spatially-blocked cross-validation procedure. The ensemble model showed moderate predictive performance (Area Under the Receiver-Operating Characteristic Curve (AUC) = 0.803 ± 0.061, True Skill Statistic (TSS) = 0.531 ± 0.100; mean ± SD), high sensitivity (92.0 ± 4.5), and offered some improvement over individual models. Substrate type, depth, and relative wave exposure were the most influential predictors associated with eelgrass occurrence, where the highest probabilities were associated with sandy and sandy-mud sediments, depths ranging 0 m – 4 m, and low to intermediate wave exposure. Within our study region, we predicted a total extent of suitable eelgrass habitat of 38,130 ha. We found suitable habitat was particularly extensive within the long narrow inlets and extensive shallow flats of the South Shore, Eastern Shore, and Bras d’Or Lakes. We also identified substantial overlap of eelgrass habitat with previously identified Ecologically and Biologically Significant Areas that guide regional conservation planning while also highlighting areas of greater prediction uncertainty arising from disagreement among modeling methods. By offering improved sensitivity and insights into the fine-scale regional distribution of a habitat-forming species with associated uncertainties, our ensemble-based modeling approach provides improved support to numerous nearshore applications including conservation planning and restoration, marine spatial and emergency response planning, environmental impact assessments, and fish habitat protection.

Shifts in competitive balance between key functional groups may drive regime shifts in tropical and temperate marine ecosystems. On shallow reefs, regime shifts increasingly involve changes from spatial dominance by foundation species (e.g. reef-building corals, canopy-forming algae) to dominance by turf-forming algae differing in structural complexity. To disentangle competitive inter actions fromother processes that may contribute to these shifts, we conducted a global meta-analysis of manipulative competition experiments between foundation and turf-forming species. Canopy-forming algae had consistently negative effects on abundance of turf-forming algae, particularly on subtidal reefs, but with a tendency towards larger effects on delicate filamentous forms compared to articulated coralline and corticated/coarsely branching turf. Competitive effects of turf-forming algae on canopy species were limited to early life-history stages, and similarly varied between turf functional groups and between subtidal and intertidal reefs. Conversely, shorter filamentous turf assemblages typical of tropical reefs had no significant effect on settlement and survival of coral larvae. Interactions between turf-forming algae and established coral colonies were negative overall, but variable in magnitude. Mean effect sizes indicated that corals suppress turf abundance, but not vice versa. However, turf-forming algae significantly impacted coral growth and tissue mortality. We suggest reefs with extensive cover of foundation species are resistant to proliferation of turf algae, but competition will inhibit recovery of reefs following disturbances that enable turf algae to establish. Therefore, competitive effects of foundation and turf-forming species must be accounted for to effectively evaluate the stability of these undesirable regime shifts and recovery potential under alternative climate and management scenarios.

We examined how large-scale disturbances that defoliate kelp beds (outbreaks of an invasive bryozoan, hurricanes) alter local-scale grazing dynamics of an abundant herbivore, the gastropod Lacuna vincta, on the Atlantic coast of Nova Scotia, Canada. From field observations and a 5 wk kelp-thinning experiment that simulated disturbance, we found that snail density and grazing intensity on the kelp Saccharina latissima increased non-linearly with decreasing kelp biomass, as it varied within a site. Grazing intensity on S. latissima also increased non-linearly with decreasing standing kelp biomass across 5 sites spanning 40 km (linear distance) of coast and 2 yr, but we did not find strong support for this relationship for the kelp Laminaria digitata. Intensification of grazing augments the indirect effect of L. vincta on S. latissima (increased blade erosion and fragmentation), and drives it beyond a threshold for further losses of kelp biomass with subsequent storms. This positive feedback between large-scale disturbances and local-scale grazing could reinforce the depletion of kelp and facilitate the establishment of turf-forming algae on Nova Scotian rocky reefs. We conclude that interactions of large external perturbations with local natural perturbations must be considered to under stand how drivers of ecosystem change collectively disrupt the balance of top-down and bottom-up forces to cause shifts to unexpected community states.

L'EMDR (désensibilisation et retraitement par les mouvements oculaires) est une thérapie qui a démontré son efficacité dans le traitement de l'état de stress post-traumatique (ESPT). Une littérature clinique encore relativement réduite, mais croissante, montre que l'EMDR peut aussi être un traitement complémentaire efficace de la toxicomanie. Le présent article passe en revue les divers protocoles qui ont été développés dans ce but, avec les protocoles de Vogelmann-Sine et al., Omaha, Popky et Hase. Une étude de cas intégrant certaines de ces interventions est présentée afin d'illustrer la réussite du traitement par l'EMDR d'une femme souffrant de longue date d'une dépendance à l'alcool et d'un ESPT comorbides. Le suivi, deux ans plus tard, a montré que cette femme restait sobre et que l'ESPT était en rémission complète. Après une discussion des aspects importants de ce cas, les auteurs explorent de futures directions de recherche.

Small invertebrate grazers can disproportionately reduce plant fitness by discriminately consuming valuable tissues, but the context and attendant consequences of this activity at higher levels of ecological organization rarely are considered. To assess the impact of a gastropod mesograzer Lacuna vincta on fecundity and potential reproductive output of the habitat‐forming kelp Saccharina latissima, we measured the intensity and distribution of grazing damage on kelp blades at five sites of varying kelp density, during the annual reproductive peak (October–November) in Nova Scotia. We found most grazing damage on reproductive individuals consisted of superficial excavations, and was concentrated on the central sorus (region where sporangia develop) compared to the vegetative blade margins. Grazing intensity on sori (percent grazed) averaged 29.6% across sites and sampling periods. The distribution of grazing on non‐reproductive individuals was opposite to that of reproductive ones, indicating that snails shift feeding from blade margins to the center as sori develop. Choice and no‐choice feeding assays in the laboratory revealed that focused grazing on sori is likely due to an active feeding preference for sporogenous over vegetative tissue. This preference was correlated with the distribution of chemical defense between tissues (phlorotannin content was