Peptides are promising drug modalities that can modulate protein–protein interactions, but their application is hampered by their limited ability to reach intracellular targets. Here, we improved the ...cytosolic delivery of a peptide blocking p53:MDM2/X interactions using a cyclotide as a stabilizing scaffold. We applied several design strategies to improve intracellular delivery and found that the conjugation of the lead cyclotide to the cyclic cell-penetrating peptide cR10 was the most effective. Conjugation allowed cell internalization at micromolar concentration and led to elevated intracellular p53 levels in A549, MCF7, and MCF10A cells, as well as inducing apoptosis in A549 cells without causing membrane disruption. The lead peptide had >35-fold improvement in inhibitory activity and increased cellular uptake compared to a previously reported cyclotide p53 activator. In summary, we demonstrated the delivery of a large polar cyclic peptide in the cytosol and confirmed its ability to modulate intracellular protein–protein interactions involved in cancer.
Medication adherence is frequently suboptimal in adults with chronic diseases, resulting in negative consequences. Motivational interviewing (MI) is a collaborative conversational style for ...strengthening a person's motivation and commitment to change. We aimed to assess whether MI interventions are effective to enhance medication adherence in adults with chronic diseases and to explore the effect of individual MI intervention characteristics.
We searched electronic databases and reference lists of relevant articles to find randomized controlled trials (RCTs) that assessed MI intervention effectiveness on medication adherence in adults with chronic diseases. A random-effects model was used to estimate a pooled MI intervention effect size and its heterogeneity (I 2 ). We also explored the effects of individual MI characteristics on MI intervention effect size using a meta-regression with linear mixed model.
: Nineteen RCTs were identified, and 16 were included in the meta-analysis. The pooled MI intervention effect size was 0.12 95% confidence interval (CI) = (0.05, 0.20), I 2 = 1%. Interventions that were based on MI only β = 0.183, 95% CI = (0.004, 0.362) or those in which interventionists were coached during intervention implementation β = 0.465, 95% CI = (0.028, 0.902) were the most effective. MI interventions that were delivered solely face to face were more effective than those that were delivered solely by phone β = 0.270, 95% CI = (0.041, 0.498).
This synthesis of RCTs suggests that MI interventions might be effective at enhancing of medication adherence in adults treated for chronic diseases. Further research is however warranted, as the observed intervention effect size was small.
Scolytinae is a subfamily of weevils that contains many major pest species. Most scolytines employ an outbreeding mating system: individuals emerge from their natal host trees and fly to new hosts, ...where they mate with unrelated conspecifics. However, in several outbreeding species, some individuals mate prior to emergence, either with a sibling or an unrelated neighbor from another gallery. Preemergence mating allows females to start adult life with a supply of sperm; they can then dig a gallery on their own in a new host tree. In this study, we examined preemergence mating in
Ips typographus
, a supposedly outbred bark beetle that causes considerable damage to European spruce forests. Our field and laboratory studies have shown that 15–94% of females are mated at (re)emergence, a wide range of values that is shaped by environmental conditions and time of year. This figure is also positively correlated with time spent under the bark. Moreover, in laboratory experiments, outbreeding females had the same level of productivity whether they established themselves with a partner or on their own. However, compared to both types of outbreeding females, solitary inbreeding females exhibited lower productivity due to higher mortality in the egg and postlarval stages, suggesting the presence of inbreeding depression. In a choice experiment, females preferentially entered nuptial chambers containing unrelated males versus brothers. These results shed new light on this bark beetle’s mating behavior, which ultimately influences the species’ ability to colonize new areas.
Abstract Since the publication of the 2012 guidelines new literature has emerged to inform decision-making. The 2016 guidelines primary panel selected a number of clinically relevant questions and ...has produced updated recommendations, on the basis of important new findings. In subjects with clinical atherosclerosis, abdominal aortic aneurysm, most subjects with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy is recommended. For all others, there is an emphasis on risk assessment linked to lipid determination to optimize decision-making. We have recommended nonfasting lipid determination as a suitable alternative to fasting levels. Risk assessment and lipid determination should be considered in individuals older than 40 years of age or in those at increased risk regardless of age. Pharmacotherapy is generally not indicated for those at low Framingham Risk Score (FRS; <10%). A wider range of patients are now eligible for statin therapy in the FRS intermediate risk category (10%-19%) and in those with a high FRS (> 20%). Despite the controversy, we continue to advocate for low-density lipoprotein cholesterol targets for subjects who start therapy. Detailed recommendations are also presented for health behaviour modification that is indicated in all subjects. Finally, recommendation for the use of nonstatin medications is provided. Shared decision-making is vital because there are many areas in which clinical trials do not fully inform practice. The guidelines are meant to be a platform for meaningful conversation between patient and care provider so that individual decisions can be made for risk screening, assessment, and treatment.
The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In ...patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.
Le panel principal responsable des lignes directrices 2021 a sélectionné des éléments cliniquement pertinents et a soumis des recommandations actualisées, basées sur de nouvelles découvertes d'importance apparues depuis les lignes directrices de 2016. Ainsi, le traitement par statine reste recommandé pour les patients atteints d'athérosclérose clinique, d'anévrisme de l'aorte abdominale, pour la plupart des patients diabétiques ou atteints d'insuffisance rénale chronique, et chez ceux dont le cholestérol à lipoprotéines de basse densité est ≥ 5 mmol/l. Nous avons introduit la notion de seuils pour le traitement des lipides/lipoprotéines afin d'intensifier le traitement hypolipidémiant avec des agents non-statiniques, et nous avons identifié les patients en prévention secondaire distingués comme ayant tirer le plus grand bénéfice de l'intensification du traitement avec ces agents. Pour tous les autres patients, nous mettons l'accent sur l'appréciation du risque par le biais de l'évaluation des lipides/lipoprotéines afin d'optimiser la prise de décision clinique. Le dosage de la lipoprotéine (a) est maintenant recommandé une fois dans la vie d'un patient, dans le cadre du dépistage initial des lipides pour évaluer le risque cardiovasculaire. Pour tout patient présentant des taux de triglycérides ˃ 1,5 mmol/l, l'apolipoprotéine B ou le cholestérol lié aux lipoprotéines autres que celles de haute densité sont les indices lipidiques à privilégier pour le dépistage, plutôt que le cholestérol à lipoprotéines de basse densité. Nous proposons des recommandations actualisées concernant le rôle du score calcique des artères coronaires en tant qu'outil de décision clinique pour aider à la décision d'administrer un traitement par statine. Il existe de nouvelles recommandations concernant les soins préventifs des femmes souffrant de troubles hypertensifs de la grossesse. Le changement de comportement en matière de santé, incluant l'exercice physique régulier et une alimentation saine pour le coeur, reste la pierre angulaire de la prévention des maladies cardiovasculaires. Ces lignes directrices visent à fournir une plateforme pour une discussion constructive et une prise de décision partagée entre le patient et le prestataire de soins, afin que des décisions individuelles puissent être prises pour le dépistage, l'évaluation et le traitement des risques.
Backing materials with tailored acoustic properties are beneficial for miniaturized ultrasonic transducer design. Whereas piezoelectric P(VDF-TrFE) films are common elements in high-frequency (>20 ...MHz) transducer design, their low coupling coefficient limits their sensitivity. Defining a suitable sensitivity-bandwidth trade-off for miniaturized high-frequency applications requires backings with impedances of >25 MRayl and strongly attenuating to account for miniaturized requirements. The motivation of this work is related to several medical applications such as small animal, skin or eye imaging. Simulations showed that increasing the acoustic impedance of the backing from 4.5 to 25 MRayl increases transducer sensitivity by 5 dB but decreases the bandwidth, which nevertheless remains high enough for the targeted applications. In this paper, porous sintered bronze material with spherically shaped grains, size-adapted for 25-30 MHz frequency, was impregnated with tin or epoxy resin to create multiphasic metallic backings. Microstructural characterizations of these new multiphasic composites showed that impregnation was incomplete and that a third air phase was present. The selected composites,
and
, at 5-35 MHz characterization, produced attenuation coefficients of 1.2 and >4 dB/mm/MHz and impedances of 32.4 and 26.4 MRayl, respectively. High-impedance composites were adopted as backing (thickness = 2 mm) to fabricate focused single-element P(VDF-TrFE)-based transducers (focal distance = 14 mm). The center frequency was 27 MHz, while the bandwidth at -6 dB was 65% for the
-based transducer. We evaluated imaging performance using a pulse-echo system on a tungsten wire (diameter = 25 μm) phantom. Images confirmed the viability of integrating these backings in miniaturized transducers for imaging applications.
Abstract
Aims
In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine ...(0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy.
Methods and results
A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy.
Conclusion
Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.
Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic ...cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.
L’hypercholestérolémie familiale (HF) est une maladie autosomique codominante caractérisée par un taux élevé de cholestérol à lipoprotéines de faible densité (cholestérol LDL) et un risque élevé de maladie cardiovasculaire athéroscléreuse prématurée. Les définitions de l’HF reposent sur des algorithmes complexes basés sur les concentrations de cholestérol total ou de cholestérol LDL, les caractéristiques cliniques, les antécédents familiaux et les analyses de l’ADN souvent difficiles à obtenir. Nous proposons une nouvelle définition simplifiée de l’HF. Pour un diagnostic définitif d'HF, il faut : 1) un taux élevé de cholestérol LDL (≥ 8,50 mmol/l) ou 2) un taux de cholestérol LDL ≥ 5,0 mmol/l (pour les 40 ans et plus); ≥ 4,0 mmol/l (pour les moins de 18 ans); ≥ 4,5 mmol/l (de 18 à 39 ans) lorsque associé à au moins l’une des caractéristiques suivantes : 1) un xanthome tendineux; ou 2) une mutation causale de l’ADN observée dans les gènes LDLR, APOB ou PCSK9 chez le propositus ou les parents de premier degré. L’HF probable concerne les sujets qui ont un taux élevé de cholestérol LDL (≥ 5,0 mmol/l) et qui montrent la présence d’une maladie cardiovasculaire athéroscléreuse prématurée chez le patient ou les parents de premier degré, ou un taux élevé de cholestérol LDL chez les parents de premier degré. Les seuils de cholestérol LDL ont été déterminés à partir d’une importante banque de données qui regroupait > 3,3 millions de sujets. En vue de comparer la définition proposée aux algorithmes actuellement utilisés (c.-à-d. le registre de Simon Broome et le Dutch Lipid Clinic Network), nous avons réalisé les analyses de concordance chez 5987 individus du Canada. La nouvelle définition de l’HF concorde très bien avec les critères du registre Simon Broome et du Dutch Lipid Clinic Network (κ = 0,969 et 0,966, respectivement). En conclusion, la définition proposée de l’HF possède une performance diagnostique comparable aux critères existants, tout en s’adaptant à la population canadienne, et facilitera le diagnostic des patients atteints d’HF.
While phylogeographic patterns of organisms are often interpreted through past environmental disturbances, mediated by climate changes, and geographic barriers, they may also be strongly influenced ...by species‐specific traits. To investigate the impact of such traits, we focused on two Eurasian spruce bark beetles that share a similar geographic distribution, but differ in their ecology and reproduction. Ips typographus is an aggressive tree‐killing species characterized by strong dispersal, whereas Dendroctonus micans is a discrete inbreeding species (sib mating is the rule), parasite of living trees and a poor disperser. We compared genetic variation between the two species over both beetles’ entire range in Eurasia with five independent gene fragments, to evaluate whether their intrinsic differences could have an influence over their phylogeographic patterns. We highlighted widely divergent patterns of genetic variation for the two species and argue that the difference is indeed largely compatible with their contrasting dispersal strategies and modes of reproduction. In addition, genetic structure in I. typographus divides European populations in a northern and a southern group, as was previously observed for its host plant, and suggests past allopatric divergence. A long divergence time was estimated between East Asian and other populations of both species, indicating their long‐standing presence in Eurasia, prior to the last glacial maximum. Finally, the strong population structure observed in D. micans for the mitochondrial locus provides insights into the recent colonization history of this species, from its native European range to regions where it was recently introduced.
In ranked-choice elections, voters vote by indicating their preference orderings over the candidates. A ballot is truncated when the ordering is incomplete (called partial voting). Sometimes ...truncation is forced—voters are allowed to rank only a limited number of candidates—but sometimes it is voluntary. During the vote tabulating process, a truncated ballot is exhausted when all of the candidates it ranks have been eliminated. Ballot exhaustion and, therefore ballot truncation, is a concern in single-winner elections when the margin of victory in the final stage is less than the number of exhausted ballots. That concern motivates our study. We review evidence from actual single-winner ranked-choice elections and conclude that voluntary ballot truncation is very common. Moreover, it is difficult to explain strategically. To assess the significance of ballot truncation, we simulate rankedchoice elections with four, five and six candidates, using both spatial and random models of voter preferences. Does truncation change the probability that a Condorcet winner wins the election? Does the winner change as the extent of truncation increases? We find that even small amounts of truncation can alter election outcomes.
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