Association of sex and cardiovascular risk factors with atherosclerosis distribution pattern in lower extremity peripheral artery disease.

Objective: Atherosclerosis expression varies across not only coronary, cerebrovascular, and peripheral arteries but also within the peripheral vascular tree. The underlying pathomechanisms of distinct atherosclerosis phenotypes in lower extremity peripheral artery disease (PAD) is poorly understood. We investigated the association of cardiovascular risk factors (CVRFs) and atherosclerosis distribution in a targeted approach analyzing symptomatic patients with isolated anatomic phenotypes of PAD. Methods: In a cross-sectional analysis of consecutive patients undergoing first-time endovascular recanalization for symptomatic PAD, data of patients with isolated anatomic phenotypes of either proximal (iliac) or distal (infrageniculate) atherosclerosis segregation were extracted. We performed a multivariable logistic regression model with backward elimination to investigate the association of proximal and distal PAD with CVRFs. Results: Of the 637 patients (29% females) with endovascular recanalization, 351 (55%) had proximal and 286 (45%) had distal atherosclerosis. Female sex [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.20-0.54, p = 0.01], active smoking (OR 0.16, 95% CI 0.09-0.28, p < 0.001), and former smoking (OR 0.33, 95% CI 0.20-0.57, p < 0.001) were associated with proximal disease. Diabetes mellitus (DM) (OR 3.25, 95% CI 1.93-5.46, p < 0.001), chronic kidney disease (CKD) (OR 1.18, 95% CI 1.08-1.28, p < 0.001), and older age (OR 1.31, 95% CI 1.06-1.61, p = 0.01) were associated with distal disease. Conclusion: Female sex, particularly in the context of smoking, is associated with clinically relevant, proximal atherosclerosis expression. Our additional findings that distal atherosclerosis expression is associated with DM, CKD, and older age suggest that PAD has at least two distinct atherosclerotic phenotypes with sex-specific and individual susceptibility to atherogenic risk factors.

Chronic in situ tissue cooling does not reduce lignification at the Swiss treeline but enhances the risk of 'blue' frost rings.

In their 2013 paper, Lenz et al. illustrated how trees growing at the low-temperature limit respond to a chronic in situ warming or cooling by 3 K, by employing Peltier-thermostated branch collars that tracked ambient temperatures. The micro-coring-based analysis of seasonal tree ring formation included double-staining microtome cross sections for lignification, but these data had not been included in the publication. In this short communication, we complement these data, collected in 2009 at the Swiss treeline, and we show that a 3 K cooling that corresponds to a 500-600 m higher elevation, had no influence on lignification. However, when a frost event occurred during the early part of ring formation, the 3 K cooling produced a blue (non-lignified) layer of cells, followed by normally lignified cells for the rest of the season. Hence, the event did not affect the cambium, but interrupted cell wall maturation in cells that were in a critical developmental stage. We conclude, that chronic cooling does not affect lignification at treeline, but it increases the risk of frost damage in premature xylem tissue.

Cost-effectiveness analysis of alternative anticoagulation in suspected heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication associated with high medical costs. Factor Xa inhibitors gradually replace approved treatment with intravenous direct thrombin inhibitors despite their off-label indication, because of easier management and favorable economic profile. Whether they are cost-effective remains unclear. We evaluated the cost-effectiveness of approved and off-label anticoagulants in patients with suspected HIT, based on census data from the largest Swiss hospital between 2015 and 2018. We constructed a decision tree model that reflects important clinical events associated with HIT. Relevant cost data were obtained from the finance department or estimated based on the Swiss-wide cost tariff. We estimated averted adverse events (AEs) and incremental cost-effectiveness ratio as primary outcome parameters. We performed deterministic and probabilistic sensitivity analyses with 2000 simulations to assess the robustness of our results. In the base-case analysis, the total cost of averting 1 AE was 49 565 Swiss francs (CHF) for argatroban, 30 380 CHF for fondaparinux, and 30 610 CHF for rivaroxaban; after adjusting for 4Ts score: 41 152 CHF (argatroban), 27 710 CHF (fondaparinux), and 37 699 CHF (rivaroxaban). Fondaparinux and rivaroxaban were more clinically effective than argatroban, with AEs averted of 0.820, 0.834, and 0.917 for argatroban, fondaparinux, and rivaroxaban, respectively. Treatment with fondaparinux resulted in less cost and more AEs averted, hence dominating argatroban. Results were most sensitive to AE rates and prolongation of stay. Monte Carlo simulations affirmed our base-case analysis. This is the first cost-effectiveness analysis comparing argatroban with fondaparinux and rivaroxaban using primary data. Fondaparinux and rivaroxaban resulted in more averted AEs, but fondaparinux had greater cost savings. Fondaparinux could be a viable alternative to argatroban.

Effect of Biomechanical Footwear on Knee Pain in People With Knee Osteoarthritis: The BIOTOK Randomized Clinical Trial.

IMPORTANCE: Individually calibrated biomechanical footwear therapy may improve pain and physical function in people with symptomatic knee osteoarthritis, but the benefits of this therapy are unclear. OBJECTIVE: To assess the effect of a biomechanical footwear therapy vs control footwear over 24 weeks of follow-up. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at a Swiss university hospital. Participants (N = 220) with symptomatic, radiologically confirmed knee osteoarthritis were recruited between April 20, 2015, and January 10, 2017. The last participant visit occurred on August 15, 2017. INTERVENTIONS: Participants were randomized to biomechanical footwear involving shoes with individually adjustable external convex pods attached to the outsole (n = 111) or to control footwear (n = 109) that had visible outsole pods that were not adjustable and did not create a convex walking surface. MAIN OUTCOMES AND MEASURES: The primary outcome was knee pain at 24 weeks of follow-up assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore standardized to range from 0 (no symptoms) to 10 (extreme symptoms). The secondary outcomes included WOMAC physical function and stiffness subscores and the WOMAC global score, all ranging from 0 (no symptoms) to 10 (extreme symptoms) at 24 weeks of follow-up, and serious adverse events. RESULTS: Among the 220 randomized participants (mean age, 65.2 years [SD, 9.3 years]; 104 women [47.3%]), 219 received the allocated treatment and 213 (96.8%) completed follow-up. At 24 weeks of follow-up, the mean standardized WOMAC pain subscore improved from 4.3 to 1.3 in the biomechanical footwear group and from 4.0 to 2.6 in the control footwear group (between-group difference in scores at 24 weeks of follow-up, -1.3 [95% CI, -1.8 to -0.9]; P < .001). The results were consistent for WOMAC physical function subscore (between-group difference, -1.1 [95% CI, -1.5 to -0.7]), WOMAC stiffness subscore (between-group difference, -1.4 [95% CI, -1.9 to -0.9]), and WOMAC global score (between-group difference, -1.2 [95% CI, -1.6 to -0.8]) at 24 weeks of follow-up. Three serious adverse events occurred in the biomechanical footwear group compared with 9 in the control footwear group (2.7% vs 8.3%, respectively); none were related to treatment. CONCLUSIONS AND RELEVANCE: Among participants with knee pain from osteoarthritis, use of biomechanical footwear compared with control footwear resulted in an improvement in pain at 24 weeks of follow-up that was statistically significant but of uncertain clinical importance. Further research would be needed to assess long-term efficacy and safety, as well as replication, before reaching conclusions about the clinical value of this device. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02363712.

Comparison Between Interwoven Nitinol and Drug Eluting Stents for Endovascular Treatment of Femoropopliteal Artery Disease.

OBJECTIVES: Information on performance of different stent platforms in endovascular revascularisation of femoropopliteal lesions is controversial and scarce. METHODS: Interwoven nitinol (INS, Supera) were compared with drug eluting (DES, Zilver PTx) stents with primary intervention for femoropopliteal lesions. The primary endpoint was time to clinically driven target lesion revascularisation (CD-TLR) within 12 months. Secondary endpoints were time to death, amputation and composite of death, amputation and CD-TLR. Due to the retrospective analysis, inverse probability treatment weighted (IPTW) Cox models were calculated to reach more similar patient populations with weights for the average treatment effect of the population. The two sensitivity analyses were propensity score matching and adjustment for covariates. RESULTS: At 12 months, the cumulative incidence of CD-TLR in the INS group (13%) and DES group (18%) did not differ (HR 1.36, 95% CI 0.56-3.31). A significant interaction between stents used and grade of calcification was observed (p = .006). HR for CD-TLR was 6.4 (95% CI 1.3-32.5) in none to mildly calcified favouring INS, and 0.3 (95% CI 0.1-1.3) for moderate to severely calcified lesions favouring DES. Stent efficiency did not differ comparing treatment of popliteal lesions (HR 0.80; 95% CI 0.21-3.13). Sensitivity analyses confirmed the primary efficacy outcome for either adjusted (HR 1.16; 95% CI 0.51-2.62) or matched analysis (HR 1.35; 95% CI 0.50-3.62)). Interaction of stents with calcification grade was lost for adjusted (HR 0.28; 95% CI 0.06-1.19) and matched analysis (HR 0.53; 95% CI 0.10-2.91). CONCLUSION: Both stents (INS and DES) showed comparable results regarding CD-TLR in femoropopliteal lesions, so that one stent could not be favoured over the other, even for calcified or popliteal artery lesions.

Levosimendan and systemic vascular resistance in cardiac surgery patients: a systematic review and meta-analysis.

Levosimendan is a potent non-adrenergic inodilator agent. The net effect of hemodynamic changes may result in a hyperdynamic state with low systemic vascular resistance. We conducted a systematic review and meta-analysis assessing hemodynamics in cardiac surgery patients treated with levosimendan. English-language literature was searched systematically from 2006 until October 2018, including randomized controlled trials and case-matched or retrospective studies providing at least two sequentially measured hemodynamic variables in adult patients who underwent cardiac surgery with cardiopulmonary bypass and were treated with levosimendan in comparison to alternative drugs or devices. Cardiac index significantly increased in the levosimendan group by 0.74 (0.24 to 1.23) [standardized mean difference (95% CI); p = 0.003] from baseline to postoperative day (POD) 1, and by 0.75 (0.25 to 1.25; p = 0.003) from baseline to POD 7, when corrected for the standardized mean difference at baseline by a multivariate mixed effects meta-analysis model. With this correction for baseline differences, other hemodynamic variables including systemic vascular resistance did not significantly differ until POD 1 [-0.17 (-0.64 to 0.30), p = 0.48] and POD 7 [-0.13 (-0.61 to 0.34), p = 0.58] between the levosimendan and the comparator group. Levosimendan increases cardiac index in patients undergoing cardiac surgery. Although levosimendan has inodilator properties, this meta-analysis finds no clinical evidence that levosimendan produces vasopressor-resistant vasoplegic syndrome.

Impact of Simulator-Based Training in Focused Transesophageal Echocardiography: A Randomized Controlled Trial.

BACKGROUND: The aim of the study was to determine if training in transesophageal echocardiography (TEE) using a TEE simulator improves the ability of novice operators to perform and interpret a focused critical care TEE. METHODS: In this prospective, randomized, controlled study with blinded outcome assessment, 44 intensive care unit trainees were randomly assigned to a control group receiving 4 hours of lecture-based training only, or an intervention group which was additionally trained for 4 hours using a TEE simulator. After the training intervention, each participant performed 2 TEEs in intensive care unit patients which were evaluated by blinded assessors. The imaging quality of TEEs was measured using a predefined examination quality score ranging from 0 to 100 points. The correct quantification of pathologies and the interpretation of the TEEs were evaluated by blinded assessors using focused and comprehensive expert TEEs as comparators. RESULTS: A total of 114 TEEs were assessed. The mean examination quality score was 55.9 (95% confidence interval [CI], 50.3-61.5) for TEEs of the control group, 75.6 (95% CI, 70.1-81.0) for TEEs of the intervention group, and 88.5 (95% CI, 79.3-97.7) for TEEs in the expert group. The multiple comparisons revealed significant differences between all groups (19.7 [95% CI, 12.8-26.6], P < .001 for intervention versus control; 32.6 [95% CI, 23.0-42.3], P < .001 for expert versus control; 12.9 [95% CI, 3.4-22.5], P = .008 for expert versus intervention). Substantial agreement of the quantification and interpretation ratings of basic TEEs by the intervention (86.7% for quantification and 97.1% for interpretation) or expert group (93.2% for quantification and 98.4% for interpretation) with blinded assessors was detected. The control groups TEEs agreed less (75.6% for quantification and 91.8% for interpretation). CONCLUSIONS: Simulation-based TEE training improves the ability of novice operators to perform a focused critical care TEE in comparison to lecture-based education only. After 8 hours of simulator and lecture-based training, the majority of TEEs of novices are of sufficient quality for clinical use. Furthermore, a substantial skill level in correct quantification and interpretation of imaging is achieved.

Frost hardening and dehardening potential in temperate trees from winter to budburst.

We investigated how deciduous trees can adjust their freezing resistance in response to temperature during the progress of the ecodormancy phase, from midwinter to budburst. We regularly sampled twigs of four different temperate deciduous tree species from January to the leaf-out date. Using computer-controlled freezers and climate chambers, the freezing resistance of buds was measured directly after sampling and also after the application of artificial hardening and dehardening treatments, simulating cold and warm spells. The thermal time to budburst in forcing conditions (c. 20°C) was also quantified at each sampling as a proxy for dormancy depth. Earlier flushing species showed higher freezing resistance than late flushing species at either similar bud development stage or similar dormancy depth. Overall, freezing resistance and its hardening and dehardening potential dramatically decreased during the progress of ecodormancy and became almost nil during budburst. Our results suggest that extreme cold events in winter are not critical for trees, as freezing resistance can be largely enhanced during this period. By contrast, the timing of budburst is a critical component of tree fitness. Our results provide quantitative values of the freezing resistance dynamics during ecodormancy, particularly valuable in process-based species distribution models.

Fast acclimation of freezing resistance suggests no influence of winter minimum temperature on the range limit of European beech.

Low temperature extremes drive species distribution at a global scale. Here, we assessed the acclimation potential of freezing resistance in European beech (Fagus sylvaticaL.) during winter. We specifically asked (i) how do beech populations growing in contrasting climates differ in their maximum freezing resistance, (ii) do differences result from genetic differentiation or phenotypic plasticity to preceding temperatures and (iii) is beech at risk of freezing damage in winter across its distribution range. We investigated the genetic and environmental components of freezing resistance in buds of adult beech trees from three different populations along a natural large temperature gradient in north-western Switzerland, including the site holding the cold temperature record in Switzerland. Freezing resistance of leaf primordia in buds varied significantly among populations, with LT50values (lethal temperature for 50% of samples) ranging from -25 to -40 °C, correlating with midwinter temperatures of the site of origin. Cambial meristems and the pith of shoots showed high freezing resistance in all three populations, with only a trend to lower freezing resistance at the warmer site. After hardening samples at -6 °C for 5 days, freezing resistance of leaf primordia increased in all provenances by up to 4.5 K. After additional hardening at -15 °C for 3 days, all leaf primordia were freezing resistant to -40 °C. We demonstrate that freezing resistance ofF. sylvaticahas a high ability to acclimate to temperature changes in winter, whereas the genetic differentiation of freezing resistance among populations seems negligible over this small geographic scale but large climatic gradient. In contrast to the assumption made in most of the species distribution models, we suggest that absolute minimum temperature in winter is unlikely to shape the cold range limit of beech. We conclude that the rapid acclimation of freezing resistance to winter temperatures allows beech to track changing climatic conditions, especially during unusually warm winters interrupted by very cold weather.

The interaction between freezing tolerance and phenology in temperate deciduous trees.

Temperate climates are defined by distinct temperature seasonality with large and often unpredictable weather during any of the four seasons. To thrive in such climates, trees have to withstand a cold winter and the stochastic occurrence of freeze events during any time of the year. The physiological mechanisms trees adopt to escape, avoid, and tolerate freezing temperatures include a cold acclimation in autumn, a dormancy period during winter (leafless in deciduous trees), and the maintenance of a certain freezing tolerance during dehardening in early spring. The change from one phase to the next is mediated by complex interactions between temperature and photoperiod. This review aims at providing an overview of the interplay between phenology of leaves and species-specific freezing resistance. First, we address the long-term evolutionary responses that enabled temperate trees to tolerate certain low temperature extremes. We provide evidence that short term acclimation of freezing resistance plays a crucial role both in dormant and active buds, including re-acclimation to cold conditions following warm spells. This ability declines to almost zero during leaf emergence. Second, we show that the risk that native temperate trees encounter freeze injuries is low and is confined to spring and underline that this risk might be altered by climate warming depending on species-specific phenological responses to environmental cues.

Physiological minimum temperatures for root growth in seven common European broad-leaved tree species.

Temperature is the most important factor driving the cold edge distribution limit of temperate trees. Here, we identified the minimum temperatures for root growth in seven broad-leaved tree species, compared them with the species' natural elevational limits and identified morphological changes in roots produced near their physiological cold limit. Seedlings were exposed to a vertical soil-temperature gradient from 20 to 2 °C along the rooting zone for 18 weeks. In all species, the bulk of roots was produced at temperatures above 5 °C. However, the absolute minimum temperatures for root growth differed among species between 2.3 and 4.2 °C, with those species that reach their natural distribution limits at higher elevations also tending to have lower thermal limits for root tissue formation. In all investigated species, the roots produced at temperatures close to the thermal limit were pale, thick, unbranched and of reduced mechanical strength. Across species, the specific root length (m g(-1) root) was reduced by, on average, 60% at temperatures below 7 °C. A significant correlation of minimum temperatures for root growth with the natural high elevation limits of the investigated species indicates species-specific thermal requirements for basic physiological processes. Although these limits are not necessarily directly causative for the upper distribution limit of a species, they seem to belong to a syndrome of adaptive processes for life at low temperatures. The anatomical changes at the cold limit likely hint at the mechanisms impeding meristematic activity at low temperatures.

European deciduous trees exhibit similar safety margins against damage by spring freeze events along elevational gradients.

Minimum temperature is assumed to be an important driver of tree species range limits. We investigated during which period of the year trees are most vulnerable to freezing damage and whether the pressure of freezing events increases with increasing elevation. We assessed the course of freezing resistance of buds and leaves from winter to summer at the upper elevational limits of eight deciduous tree species in the Swiss Alps. By reconstructing the spring phenology of these species over the last eight decades using a thermal time model, we linked freezing resistance with long-term minimum temperature data along elevational gradients. Counter-intuitively, the pressure of freeze events does not increase with elevation, but deciduous temperate tree species exhibit a constant safety margin (5-8.5 K) against damage by spring freeze events along elevational gradients, as a result of the later flushing at higher elevation. Absolute minimum temperatures in winter and summer are unlikely to critically injure trees. Our study shows that freezing temperatures in spring are the main selective pressure controlling the timing of flushing, leading to a shorter growing season at higher elevation and potentially driving species distribution limits. Such mechanistic knowledge is important to improve predictions of tree species range limits.

Elevational adaptation and plasticity in seedling phenology of temperate deciduous tree species.

Phenological events, such as the initiation and the end of seasonal growth, are thought to be under strong evolutionary control because of their influence on tree fitness. Although numerous studies highlighted genetic differentiation in phenology among populations from contrasting climates, it remains unclear whether local adaptation could restrict phenological plasticity in response to current warming. Seedling populations of seven deciduous tree species from high and low elevations in the Swiss Alps were investigated in eight common gardens located along two elevational gradients from 400 to 1,700 m. We addressed the following questions: are there genetic differentiations in phenology between populations from low and high elevations, and are populations from the upper elevational limit of a species' distribution able to respond to increasing temperature to the same extent as low-elevation populations? Genetic variation of leaf unfolding date between seedlings from low and high populations was detected in six out of seven tree species. Except for beech, populations from high elevations tended to flush later than populations from low elevations, emphasizing that phenology is likely to be under evolutionary pressure. Furthermore, seedlings from high elevation exhibited lower phenological plasticity to temperature than low-elevation provenances. This difference in phenological plasticity may reflect the opposing selective forces involved (i.e. a trade-off between maximizing growing season length and avoiding frost damages). Nevertheless, environmental effects were much stronger than genetic effects, suggesting a high phenological plasticity to enable tree populations to track ongoing climate change, which includes the risk of tracking unusually warm springs followed by frost.