More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles.

Introduction: Many loci segregate alleles classified as "genetic diseases" due to their deleterious effects on health. However, some disease alleles have been reported to show beneficial effects under certain conditions or in certain populations. The beneficial effects of these antagonistically pleiotropic alleles may explain their continued prevalence, but the degree to which antagonistic pleiotropy is common or rare is unresolved. We surveyed the medical literature to identify examples of antagonistic pleiotropy to help determine whether antagonistic pleiotropy appears to be rare or common. Results: We identified ten examples of loci with polymorphisms for which the presence of antagonistic pleiotropy is well supported by detailed genetic or epidemiological information in humans. One additional locus was identified for which the supporting evidence comes from animal studies. These examples complement over 20 others reported in other reviews. Discussion: The existence of more than 30 identified antagonistically pleiotropic human disease alleles suggests that this phenomenon may be widespread. This poses important implications for both our understanding of human evolutionary genetics and our approaches to clinical treatment and disease prevention, especially therapies based on genetic modification.

Advanced Practice Providers as Leaders of a Rapid Response Team: A Prospective Cohort Study.

In view of the shortage of medical staff, the quality and continuity of care may be improved by employing advanced practice providers (APPs). This study aims to assess the quality of these APPs in critical care. In a large teaching hospital, rapid response team (RRT) interventions led by APPs were assessed by independent observers and intensivists and compared to those led by medical residents MRs. In addition to mortality, the MAELOR tool (assessment of RRT intervention), time from RRT call until arrival at the scene and time until completion of clinical investigations were assessed. Process outcomes were assessed with the crisis management skills checklist, the Ottawa global rating scale and the Mayo high-performance teamwork scale. The intensivists assessed performance with the handoff CEX recipient scale. Mortality, MAELOR tool, time until arrival and clinical investigation in both groups were the same. Process outcomes and performance observer scores were also equal. The CEX recipient scores, however, showed differences between MRs and APPs that increased with experience. Experienced APPs had significantly better situational awareness, better organization, better evaluations and better judgment than MRs with equal experience (p < 0.05). This study shows that APPs perform well in leading an RRT and may provide added quality over a resident. RRTs should seriously consider the deployment of APPs instead of junior clinicians.

Quality Improvement in the Preoperative Evaluation: Accuracy of an Automated Clinical Decision Support System to Calculate CHA2DS2-VASc Scores.

Background and Objectives: Clinical decision support systems are advocated to improve the quality and efficiency in healthcare. However, before implementation, validation of these systems needs to be performed. In this evaluation we tested our hypothesis that a computerized clinical decision support system can calculate the CHA2DS2-VASc score just as well compared to manual calculation, or even better and more efficiently than manual calculation in patients with atrial rhythm disturbances. Materials and Methods: In n = 224 patents, we calculated the total CHA2DS2-VASc score manually and by an automated clinical decision support system. We compared the automated clinical decision support system with manually calculation by physicians. Results: The interclass correlation between the automated clinical decision support system and manual calculation showed was 0.859 (0.611 and 0.931 95%-CI). Bland-Altman plot and linear regression analysis shows us a bias of -0.79 with limit of agreement (95%-CI) between 1.37 and -2.95 of the mean between our 2 measurements. The Cohen's kappa was 0.42. Retrospective analysis showed more human errors than algorithmic errors. Time it took to calculate the CHA2DS2-VASc score was 11 s per patient in the automated clinical decision support system compared to 48 s per patient with the physician. Conclusions: Our automated clinical decision support system is at least as good as manual calculation, may be more accurate and is more time efficient.

Advanced practice providers versus medical residents as leaders of rapid response teams: A 12-month retrospective analysis.

PURPOSE: In a time of worldwide physician shortages, the advanced practice providers (APPs) might be a good alternative for physicians as the leaders of a rapid response team. This retrospective analysis aimed to establish whether the performance of APP-led rapid response teams is comparable to the performance of rapid response teams led by a medical resident of the ICU. MATERIAL AND METHODS: In a retrospective single-center cohort study, the electronic medical record of a tertiary hospital was queried during a 12-months period to identify patients who had been visited by our rapid response team. Patient- and process-related outcomes of interventions of rapid response teams led by an APP were compared with those of teams led by a medical resident using various parameters, including the MAELOR tool, which measures the performance of a rapid response team. RESULTS: In total, 179 responses of the APP-led teams were analyzed, versus 275 responses of the teams led by a resident. Per APP, twice as many calls were handled than per resident. Interventions of teams led by APPs, and residents did not differ in number of admissions (p = 0.87), mortality (p = 0.8), early warning scores (p = 0.2) or MAELOR tool triggering (p = 0.19). Both groups scored equally on time to admission (p = 0.67) or time until any performed intervention. CONCLUSION: This retrospective analysis showed that the quality of APP-led rapid response teams was similar to the quality of teams led by a resident. These findings need to be confirmed by prospective studies with balanced outcome parameters.

Effect of Automated Closed-loop ventilation versus convenTional VEntilation on duration and quality of ventilation in critically ill patients (ACTiVE) - study protocol of a randomized clinical trial.

BACKGROUND: INTELLiVENT-Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT-ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT-ASV shortens time spent on a ventilator and improves the quality of breathing. METHODS: The "Effects of Automated Closed-loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation" (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of > 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT-ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days. DISCUSSION: ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation. TRIAL REGISTRATION: ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810 ) on 20 October 2020.

Diagnostic performance of echocardiography to predict cardiac tamponade after cardiac surgery.

OBJECTIVES: Cardiac tamponade is a life-threatening complication after cardiac surgery. Echocardiography, both transthoracic (TTE) and transesophageal (TEE), may help to identify cardiac tamponade after surgery, but its diagnostic value remains unverified after cardiac surgery. METHODS: This retrospective single-centre cohort study used the electronic medical record and echocardiography database of the Catharina Hospital Eindhoven, a tertiary referral cardiothoracic centre, to identify patients who received echocardiography because they were clinically suspected of having cardiac tamponade within the 4 weeks after cardiac surgery. Overall diagnostic accuracy of both TTE and TEE was calculated (sensitivity, specificity, positive predictive value, negative predictive value, and receiver operation characteristics curves). Subgroup analyses were performed based on the timing of the echocardiography after primary surgery (<24, 24-72, >72 h). RESULTS: The query identified 427 echocardiographs, 373 TTEs and 54 TEEs, being performed in 414 patients (65% males, mean age 67 years). Of them, 116 patients underwent surgical re-exploration in which a cardiac tamponade was determined in 105 patients with a 30-day mortality of 8.6%. The area under the receiver operation characteristics curve for echocardiography in the 4 weeks after cardiac surgery was 0.78 [95% confidence interval (CI): 0.72-0.84, P < 0.001]. In the first 24 h after surgery was the positive predictive value of echocardiography 58.3% (95% CI: 28.6-83.5) with an area under the curve of 0.64 (95% CI: 0.49-0.80, P = 0.06). The diagnostic accuracy improved over time for both TTE and TEE. CONCLUSIONS: Diagnostic accuracy of echocardiography in the 4 weeks after cardiac surgery for cardiac tamponade is acceptable and improves over time. However, in the early postoperative phase (<24 h), the diagnostic accuracy of echocardiography is poor.

Intelligent checklists improve checklist compliance in the intensive care unit: a prospective before-and-after mixed-method study.

BACKGROUND: We examined whether a context and process-sensitive 'intelligent' checklist increases compliance with best practice compared with a paper checklist during intensive care ward rounds. METHODS: We conducted a single-centre prospective before-and-after mixed-method trial in a 35 bed medical and surgical ICU. Daily ICU ward rounds were observed during two periods of 8 weeks. We compared paper checklists (control) with a dynamic (digital) clinical checklist (DCC, intervention). The primary outcome was compliance with best clinical practice, measured as the percentages of checked items and unchecked critical items. Secondary outcomes included ICU stay and the usability of digital checklists. Data are presented as median (interquartile range). RESULTS: Clinical characteristics and severity of critical illness were similar during both control and intervention periods of study. A total of 36 clinicians visited 197 patients during 352 ward rounds using the paper checklist, compared with 211 patients during 366 ward rounds using the DCC. Per ICU round, a median of 100% of items (94.4-100.0) were completed by DCC, compared with 75.1% (66.7-86.4) by paper checklist (P=0.03). No critical items remained unchecked by the DCC, compared with 15.4% (8.3-27.3) by the paper checklist (P=0.01). The DCC was associated with reduced ICU stay (1 day [1-3]), compared with the paper checklist (2 days [1-4]; P=0.05). Usability of the DCC was judged by clinicians to require further improvement. CONCLUSIONS: A digital checklist improved compliance with best clinical practice, compared with a paper checklist, during ward rounds on a mixed ICU. CLINICAL TRIAL REGISTRATION: NCT03599856.

Fully automated postoperative ventilation in cardiac surgery patients: a randomised clinical trial.

BACKGROUND: Ensuring that lung-protective ventilation is achieved at scale is challenging in perioperative practice. Fully automated ventilation may be more effective in delivering lung-protective ventilation. Here, we compared automated lung-protective ventilation with conventional ventilation after elective cardiac surgery in haemodynamically stable patients. METHODS: In this single-centre investigator-led study, patients were randomly assigned at the end of cardiac surgery to receive either automated (adaptive support ventilation) or conventional ventilation. The primary endpoint was the proportion of postoperative ventilation time characterised by exposure to predefined optimal, acceptable, and critical (injurious) ventilatory parameters in the first three postoperative hours. Secondary outcomes included severe hypoxaemia (Spo2 <85%) and resumption of spontaneous breathing. Data are presented as mean (95% confidence intervals [CIs]). RESULTS: We randomised 220 patients (30.4% females; age: 62-76 yr). Subjects randomised to automated ventilation (n=109) spent a 29.7% (95% CI: 22.1-37.4) higher mean proportion of postoperative ventilation time receiving optimal postoperative ventilation after surgery (P<0.001) compared with subjects receiving conventional postoperative ventilation (n=111). Automated ventilation also reduced the proportion of postoperative ventilation time that subjects were exposed to injurious ventilatory settings by 2.5% (95% CI: 1-4; P=0.003). Severe hypoxaemia was less likely in subjects randomised to automated ventilation (risk ratio: 0.26 [0.22-0.31]; P<0.01). Subjects resumed spontaneous breathing more rapidly when randomised to automated ventilation (hazard ratio: 1.38 [1.05-1.83]; P=0.03). CONCLUSIONS: Fully automated ventilation in haemodynamically stable patients after cardiac surgery optimised lung-protective ventilation during postoperative ventilation, with fewer episodes of severe hypoxaemia and an accelerated resumption of spontaneous breathing. CLINICAL TRIAL REGISTRATION: NCT03180203.

The correlation of age with chemotherapy-induced ovarian function failure in breast cancer patients.

PURPOSE: To assess the incidence of chemotherapy-induced ovarian function failure (COFF) based on estradiol and follicle stimulating hormone (FSH) monitoring in premenopausal women with hormone-receptor positive breast cancer treated with second and third generation (neo-)adjuvant chemotherapy. RESULTS: We identified 115 eligible women. Two years after start of chemotherapy, COFF was significantly more often present in women ≥ 40 years (85.6%) as compared to women < 40 years (8.7%). Only age was significantly associated with COFF two years after start of chemotherapy (HR 12.26; 95% CI 5.21-28.86). In 50% of the patients, premenopausal hormone levels were the first or only evidence of ovarian function recovery (OFR). MATERIALS AND METHODS: We included all premenopausal women with hormone-receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without taxanes, in our university hospital in the Netherlands in the years 2005-2013. Patients were 3-monthly monitored for ovarian function. Cox proportional hazards model was used to determine the predictive impact of various parameters on the occurrence of COFF. CONCLUSIONS: After second- or third generation (neo-)adjuvant chemotherapy, COFF was still present in 8.7% of patients < 40 years after two years. FSH and estradiol monitoring may be relevant for those in whom ovarian function suppression is considered an additional effective endocrine treatment.

Strong nonlinear selection against fluctuating asymmetry in wild populations of a marine fish.

Theoretical links between fluctuating asymmetry (FA) and fitness have led many to use FA as a proxy for average fitness. However, studies examining whether asymmetry actually correlates with individual fitness in wild populations are relatively rare and often use simple measures of association (e.g., correlation coefficients). Consequently, the pattern of selection on asymmetry in the wild is seldom clear. We examined selection on FA of pectoral fin morphology in two wild populations of a marine fish (the kelp perch; Brachyistius frenatus). As expected, variance in signed FA in each initial sample was significantly greater than that found in the surviving population, indicating selection against FA. Our estimate of the fitness surface confirmed perfect symmetry as the phenotypic optimum and indicated strong, nonlinear selection against asymmetry. No difference in the form of selection was detected between populations. However, the level of FA in the initial samples varied among populations, leading to an overall difference in the level of selective mortality. Our results suggest that selection on asymmetry in wild populations may be strongly nonlinear, and indicate that the demographic costs of asymmetry may play a substantial role in the dynamics of populations.

An analysis of discrepancies between United Kingdom cancer research funding and societal burden and a comparison to previous and United States values.

BACKGROUND: Ideally, the allocation of research funding for each specific type of cancer should be proportional to its societal burden. This burden can be estimated with the metric 'years of life lost' (YLL), which combines overall mortality and age at death. METHODS: Using United Kingdom data from 2010, we compared research funding from the National Cancer Research Institute to this YLL burden metric for 26 types of cancers in order to identify the discrepancies between cancer research funding allocation and societal burden. We also compared these values to United States data from 2010 and United Kingdom data published in 2005. RESULTS: Our study revealed a number of discrepancies between cancer research funding and burden. Some cancers are funded at levels far higher than their relative burden suggests (testicular, leukaemia, Hodgkin's lymphoma, breast, cervical, ovarian, prostate) while other cancers appear under-funded (gallbladder, lung, nasopharyngeal, intestine, stomach, pancreatic, thyroid, oesophageal, liver, kidney, bladder, and brain/central nervous system). United Kingdom funding patterns over the past decade have generally moved to increase funding to previously under-funded cancers with one notable exception showing a converse trend (breast cancer). The broad relationship between United Kingdom and United States funding patterns is similar with a few exceptions (e.g. leukaemia, Hodgkin's lymphoma, prostate, testicular cancer). CONCLUSIONS: There are discrepancies between cancer research funding allocation and societal burden in the United Kingdom. These discrepancies are broadly similar in both the United Kingdom and the United States and, while they appear to be improving, this is not consistent across all types of cancer.

An evaluation of resource utilisation of single stage porcine acellular dermal matrix assisted breast reconstruction: A comparative study.

OBJECTIVES: To evaluate resource utilization of single stage porcine acellular dermal matrix (ADM) assisted breast reconstruction compared with tissue expander (TE), latissimus dorsi flap and implant (LD/I) and latissimus dorsi flap and TE (LD/TE) reconstructive techniques. MATERIALS AND METHODS: Clinical data was collected for length of stay, operative time, additional hospitalisations and operative procedures, and outpatient appointments for 101 patients undergoing unilateral implant based breast reconstruction. Resources utilised by ADM (Strattice Reconstructive Tissue Matrix™) patients were analysed and compared to the resource usage of traditional techniques. RESULTS: 25 patients undergoing single stage ADM (ADM/I) were compared with 27 having TE, 32 having LD/I and 17 having LD/TE reconstructions. Follow up was 24 months. Compared to TE, ADM/I had similar length of stay and operative time, lower rate and number of additional procedures, fewer, shorter re-admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/TE, ADM/I had shorter length of stay and operative time (p < 0.05), lower rate and number of additional procedures, fewer, shorter re-admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/I, ADM/I had shorter length of stay (p < 0.05) and operative time (p < 0.05), fewer appointments, similar rate and number of additional procedures but required more and longer re-admissions. CONCLUSION: In our experience, unilateral single stage ADM/I was associated with fewer resources utilised in comparison with two staged TE and LD/TE reconstructions in both complication-free and complicated settings over a 24-month period, despite requiring aesthetic revision in 60.9% of patients. Compared to LD/I, resource utilisation was commensurate in complication-free and complicated settings.

Influence of Inbreeding on Female Mate Choice in Two Species of Drosophila.

Many organisms have been reported to choose their mates in order to increase the heterozygosity of their offspring by avoiding mating with relatives or homozygous individuals. Most previous studies using Drosophila melanogaster have used artificial chromosomes or extreme inbreeding treatments, situations unlikely to be matched in nature. Additionally, few studies have examined the interaction between female inbreeding status and her choice of mate. Using females and males from populations that had experienced either random mating or one generation of sib-sib inbreeding, we measured the preferences of females for males. Our results indicate that outbred males were chosen more often than inbred males and that this preference may be more pronounced in outbred females than in inbred ones.

A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding.

BACKGROUND: Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; "Years of Life Lost" (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. METHODS: Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. RESULTS: Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). CONCLUSIONS: These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden.

Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles.

BACKGROUND: Many serious diseases have a genetic basis which, from an evolutionary point of view, should have been selected against, resulting in very low frequencies. The remarkable sustained prevalence of a number of disease-associated alleles is therefore surprising. We believe that antagonistic pleiotropy, when multiple effects of a gene have opposing effects on fitness (e.g., sickle cell disease), may be more widespread than typically considered. We hypothesize that, rather than being an exception to the rule of genetic disorders, antagonistic pleiotropy may be common. METHODS: We surveyed the medical literature in order to determine whether sufficient evidence exists to reassess the nature of antagonistic pleiotropy; from being considered an unusual scenario to one that is anticipated. We also used a simple population genetic model to examine the feasibility of antagonistic pleiotropy to act as a mechanism to maintain polymorphism for serious genetic disorders even if the benefits are subtle. RESULTS: We identified a number of examples of antagonistic pleiotropy where the deleterious effect, the beneficial effect, and the exact molecular cause have been demonstrated. We also identified putative cases in which there is circumstantial evidence or a strong reason to expect antagonistic pleiotropy in a genetic disorder. The population genetic model demonstrates that alleles with severe deleterious health effects can be maintained at medically relevant frequencies with only minor beneficial pleiotropic effects. CONCLUSION: We believe that our identification of several cases of antagonistic pleiotropy, despite the lack of research on this question and the varied natures of the types of these disorders, speaks to both the underappreciated nature of this phenomenon and its potentially fundamental importance. If antagonistic pleiotropy is as common as our research suggests, this may explain why so many serious diseases, even apparently environmentally caused ones, have a genetic component. Furthermore, acceptance of a genome full of antagonistically pleiotropic genetic interactions poses important implications for clinical treatment and disease prevention research, especially genetically based therapies.

Working length determination in general dental practice: a randomised controlled trial.

OBJECTIVE: To evaluate the ability of apex locators as a tool in determining working length in comparison to traditional working length radiographs in general dental practice. DESIGN: Randomised controlled clinical trial. SETTING: General dental practices in the North West of England.Subjects Adults requiring root canal treatment of at least one tooth with minimal or moderate difficulty. INTERVENTION: Root canal treatment was carried out with the working length determined by apex locator in the treatment group (AL), and periapical radiograph in the control group (PA). OUTCOME MEASURE: The acceptability of the master cone gutta percha measured from a radiograph before obturation was used as the primary outcome. RESULTS: Twenty-one of 23 fillings in the AL group were judged as acceptable, compared to 17 of 23 fillings in the PA group. This difference was not statistically significant. CONCLUSION: In general dental practice, no significant difference was found in working length determined using apex locator combined with a master cone GP radiograph or using the conventional method. There is a need for larger trials to investigate these methods further.

Artificial selection reveals heritable variation for developmental instability.

Fluctuating (nondirectional) asymmetry (FA) of bilaterally paired structures on a symmetrical organism is commonly used to assay the developmental instability (DI) caused by environmental or genetic factors. Although evidence for natural selection to reduce FA has been reported, evidence that FA (and by extension DI) is heritable is weak. We report the use of artificial selection to demonstrate heritable variation in the fluctuating asymmetry of interlandmark distances within the wing in an outbred population of Drosophila melanogaster. Our estimates for the heritability of FA range from 0% to 1% and result in estimates for the heritability of DI as large as 20%, comparable to values typical for life-history traits. These values indicate the existence of evolutionarily relevant genetic variation for DI and the effectiveness of selection for reduced FA suggests that natural selection has not fixed all the genetic variants that would improve developmental stability in these populations.

Patient assessment in general dental practice - risk assessment or clinical monitoring?

Risk assessment in general dental practice is becoming increasingly common and has led to the development of care protocols, which aim to act as a framework for decision making to produce an optimum level of care. However, many models of risk have been informed by research undertaken in academia and are based upon summary statistics of populations. In practice, a significant proportion of patients attend on a non-symptomatic, continuous and regular basis, often over long periods of time. This provides general dental practitioners with a wealth of knowledge about their patients to inform clinical decision making on an individual basis. The purpose of this paper is to highlight the important differences between an academic assessment of risk and one that is relevant to practice, before introducing a simple tool to screen out patients who are considered to be 'low risk'. The relevance of this tool is discussed, along with its potential uses and limitations as a means to promote discussion during the development of the pilots for the new dental contract to be introduced by the coalition government.

Evolution of variation and variability under fluctuating, stabilizing, and disruptive selection.

How variation and variability (the capacity to vary) may respond to selection remain open questions. Indeed, effects of different selection regimes on variational properties, such as canalization and developmental stability are under debate. We analyzed the patterns of among- and within-individual variation in two wing-shape characters in populations of Drosophila melanogaster maintained under fluctuating, disruptive, and stabilizing selection for more than 20 generations. Patterns of variation in wing size, which was not a direct target of selection, were also analyzed. Disruptive selection dramatically increased phenotypic variation in the two shape characters, but left phenotypic variation in wing size unaltered. Fluctuating and stabilizing selection consistently decreased phenotypic variation in all traits. In contrast, within-individual variation, measured by the level of fluctuating asymmetry, increased for all traits under all selection regimes. These results suggest that canalization and developmental stability are evolvable and presumably controlled by different underlying genetic mechanisms, but the evolutionary responses are not consistent with an adaptive response to selection on variation. Selection also affected patterns of directional asymmetry, although inconsistently across traits and treatments.