Social regulation of reproduction: control or signal?

Traditionally, dominant breeders have been considered to be able to control the reproduction of other individuals in multimember groups that have high variance in reproductive success/reproductive skew (e.g., forced sterility/coercion of conspecifics in eusocial animals; sex-change suppression in sequential hermaphrodites). These actions are typically presented as active impositions by reproductively dominant individuals. However, how can individuals regulate the reproductive physiology of others? Alternatively, all contestants make reproductive decisions, and less successful individuals self-downregulate reproduction in the presence of dominant breeders. Shifting perspective from a top-down manipulation to a broader view, which includes all contenders, and using a multitaxon approach, we propose a unifying framework for the resolution of reproductive skew conflicts based on signalling rather than control, along a continuum of levels of strategic regulation of reproduction.

The oxidative cost of competing for egg fertilization exceeds the cost of egg production.

Measuring reproductive costs is crucial to understanding sexual conflict and its evolutionary outcomes. Sexual conflict is thought to originate from anisogamy-the size difference between male and female gametes; if sperm are tiny and not produced in vastly greater numbers than eggs, at any mating females' gametic investment is larger than that of males. Testing this prediction has proven difficult, especially because males and females differ in many more traits than just gamete size. We overcame this difficulty by exposing simultaneously hermaphroditic polychaete worms Ophryotrocha diadema (two sexual functions in the same body) to two social conditions, pairs, and groups >2, where hermaphrodites invest either relatively more in the female function or relatively more in the male function, respectively. Then we measured four markers of cellular oxidative status, a physiological mediator of life-history strategies. Less female-biased hermaphrodites produced fewer eggs but, unexpectedly, had lower levels of antioxidant protection than more female-biased hermaphrodites, which produced more eggs. Male-biased hermaphrodites compete for mating as males (hermaphrodites in pairs do not) suggesting that in the short-term male competition might be costlier than egg production in terms of regulation of oxidative status. These results highlight the need of including behavioral traits, namely competition over egg fertilization, in the measures of reproductive costs.

Genome and cuticular hydrocarbon-based species delimitation shed light on potential drivers of speciation in a Neotropical ant species complex.

Geographic separation that leads to the evolution of reproductive isolation between populations generally is considered the most common form of speciation. However, speciation may also occur in the absence of geographic barriers due to phenotypic and genotypic factors such as chemical cue divergence, mating signal divergence, and mitonuclear conflict. Here, we performed an integrative study based on two genome-wide techniques (3RAD and ultraconserved elements) coupled with cuticular hydrocarbon (CHC) and mitochondrial (mt) DNA sequence data, to assess the species limits within the Ectatomma ruidum species complex, a widespread and conspicuous group of Neotropical ants for which heteroplasmy (i.e., presence of multiple mtDNA variants in an individual) has been recently discovered in some populations from southeast Mexico. Our analyses indicate the existence of at least five distinct species in this complex: two widely distributed across the Neotropics, and three that are restricted to southeast Mexico and that apparently have high levels of heteroplasmy. We found that species boundaries in the complex did not coincide with geographic barriers. We therefore consider possible roles of alternative drivers that may have promoted the observed patterns of speciation, including mitonuclear incompatibility, CHC differentiation, and colony structure. Our study highlights the importance of simultaneously assessing different sources of evidence to disentangle the species limits of taxa with complicated evolutionary histories.

Chemically Insignificant Social Parasites Exhibit More Anti-Dehydration Behaviors than Their Hosts.

Social parasites have evolved adaptations to overcome host resistance as they infiltrate host colonies and establish there. Among the chemical adaptations, a few species are chemically "insignificant"; they are poor in recognition cues (cuticular hydrocarbons) and evade host detection. As cuticular hydrocarbons also serve a waterproofing function, chemical insignificance is beneficial as it protects parasites from being detected but is potentially harmful because it exposes parasites to desiccation stress. Here I tested whether the social parasites Polistes atrimandibularis employ behavioral water-saving strategies when they live at Polistes biglumis colonies. Observations in the field showed that parasites were less active than their cohabiting host foundresses, spent more time at the nest, and rested in the shadowy, back face of the nest, rather than at the front face, which contradicted expectations for the use of space for dominant females-typically, dominants rest at the nest front-face. These data suggest that behavioral adaptations might promote resistance to desiccation stress in chemical insignificant social parasites.

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1.

OBJECTIVE: Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. METHODS: In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. RESULTS: Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. CONCLUSIONS: Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

Egg-trading worms start reciprocation with caution, respond with confidence and care about partners' quality.

Conditional reciprocity (help someone who helped you before) explains the evolution of cooperation among unrelated individuals who take turns helping each other. Reciprocity is vulnerable to exploitations, and players are expected to identify uncooperative partners who do not return the help they received. We tested this prediction in the simultaneously hermaphroditic worm, Ophryotrocha diadema, which engages in mutual egg donations by alternating sexual roles (one worm releases' eggs and the other fertilizes them). We set up dyads with different cooperativeness expectations; partners were either the same or a different body size (body size predicts clutch size). Large worms offered larger clutches and did so sooner when paired with large rather than small partners. They also released smaller egg clutches when they started egg donations than when they responded to a partners' donation, fulfilling the prediction that a players' first move will be prudent. Finally, behavioral bodily interactions were more frequent between more size-dissimilar worms, suggesting that worms engaged in low-cost behavioral exchanges before investing in such costly moves as egg donations. These results support the hypothesis that simultaneously hermaphroditic worms follow a conditional reciprocity paradigm and solve the conflict over sexual roles by sharing the costs of reproduction via the male and the female functions.

A Stresipteran parasite extends the lifespan of workers in a social wasp.

In social wasps, female lifespan depends on caste and colony tasks: workers usually live a few weeks while queens as long as 1 year. Polistes dominula paper wasps infected by the strepsipteran parasite Xenos vesparum avoid all colony tasks, cluster on vegetation where parasite dispersal and mating occur, hibernate and infect the next generation of wasp larvae. Here, we compared the survival rate of infected and uninfected wasp workers. Workers' survival was significantly affected by parasite sex: two-third of workers parasitized by a X. vesparum female survived and overwintered like future queens did, while all workers infected by a X. vesparum male died during the summer, like uninfected workers that we used as controls. We measured a set of host and parasite traits possibly associated with the observed lifespan extension. Infected overwintering workers had larger fat bodies than infected workers that died in the summer, but they had similar body size and ovary development. Furthermore, we recorded a positive correlation between parasite and host body sizes. We hypothesize that the manipulation of worker's longevity operated by X. vesparum enhances parasite's fitness: if workers infected by a female overwinter, they can spread infective parasite larvae in the spring like parasitized gynes do, thus contributing to parasite transmission.

Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma.

Aim: Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Materials & methods: Relevant studies were identified via a systematic literature review. Results: About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Conclusion: Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making.

Strong Gene Flow Undermines Local Adaptations in a Host Parasite System.

The co-evolutionary pathways followed by hosts and parasites strongly depend on the adaptive potential of antagonists and its underlying genetic architecture. Geographically structured populations of interacting species often experience local differences in the strength of reciprocal selection pressures, which can result in a geographic mosaic of co-evolution. One example of such a system is the boreo-montane social wasp Polistes biglumis and its social parasite Polistes atrimandibularis, which have evolved local defense and counter-defense mechanisms to match their antagonist. In this work, we study spatial genetic structure of P. biglumis and P. atrimandibularis populations at local and regional scales in the Alps, by using nuclear markers (DNA microsatellites, AFLP) and mitochondrial sequences. Both the host and the parasite populations harbored similar amounts of genetic variation. Host populations were not genetically structured at the local scale, but geographic regions were significantly differentiated from each other in both the host and the parasite in all markers. The net dispersal inferred from genetic differentiation was similar in the host and the parasite, which may be due to the annual migration pattern of the parasites between alpine and lowland populations. Thus, the apparent dispersal barriers (i.e., high mountains) do not restrict gene flow as expected and there are no important gene flow differences between the species, which contradict the hypothesis that restricted gene flow is required for local adaptations to evolve.

An indirect treatment comparison of the efficacy of pembrolizumab versus competing regimens for the adjuvant treatment of stage III melanoma.

Objective: To determine the efficacy of pembrolizumab relative to other treatments used in stage III melanoma by conducting a systematic literature review (SLR) and network meta-analysis (NMA). Methods: A SLR was conducted to identify randomized clinical trials (RCTs) evaluating approved adjuvant treatments including interferon-containing regimens, BRAF-inhibitors, and PD-L1 inhibitors in stage III melanoma patients. Relative treatment effects for recurrence-free survival (RFS) were synthesized with Bayesian NMA models that allowed for hazard ratios (HRs) to vary over time. Results: Included studies formed a connected network of evidence composed of eight trials. In high-risk stage III patients, the HR for pembrolizumab vs observation decreased significantly over time with the superiority of pembrolizumab over observation becoming statistically meaningful before 3 months. By 9 months, the HR for pembrolizumab vs observation was statistically significantly lower than the HR for most other treatments vs observation, with the exception of ipilimumab and biochemotherapy due to overlapping 95% credible intervals. In BRAF + patients, pembrolizumab was statistically significantly better than observation after 3 months. The HR for both BRAF-inhibitors vs observation increased significantly over time and pembrolizumab was statistically superior to both BRAF-inhibitors after 15 months. Conclusions: Pembrolizumab results in statistically significantly improved RFS compared to all competing regimens after 9 months, except ipilimumab and biochemotherapy, for the adjuvant treatment of stage III melanoma. However, point estimate HRs vs observation for pembrolizumab are much lower than those for ipilimumab. In BRAF + patients, the advantage of pembrolizumab versus competing interventions increases over time with respect to RFS.

Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1.

INTRODUCTION: Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1. METHODS: Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches. RESULTS: Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1-12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1-1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0-3.6) and RR was 1.6 (95% CI 1.4-1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6-5.3) and RR was 1.4 (95% CI 1.2-1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1-1.9), 1.5 (95% CI 1.1-2.5), and 1.2 (95% CI 1.0-1.5); RRs 4.2 (95% CI 2.6-6.7), 7.8 (95% CI 3.6-17.0), and 11.2 (95% CI 5.1-24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach. CONCLUSION: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones. FUNDING: AveXis.

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.

AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC). PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.

Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy.

PURPOSE: While statins are used as first-line treatments for high-risk patients with hypercholesterolemia, statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol (LDL-C) levels. Second-line treatment options include up-titration of statin dose, switching to a more potent statin, or combination therapy, e.g., with ezetimibe. The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease (CVD) and who had been previously treated with a statin. METHODS: A systematic literature search was performed and evidence bases were established for populations of atorvastatin-, simvastatin-, and rosuvastatin-experienced patients using eligible randomized controlled trials (RCTs). Based on the available data, we constructed networks of evidence and conducted a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome of interest was percent change from baseline in LDL-C. Changes in total cholesterol were explored as a secondary outcome. FINDINGS: Across all patient populations, 35 RCTs were identified and included in the evidence base. Among patients on simvastatin therapy, the addition of ezetimibe resulted in a mean difference (MD) in LDL-C of - 13.62% (95% CrI - 19.99, - 6.91; see table below) compared to doubling the starting dose of simvastatin. In the population of patients on atorvastatin therapy, the addition of ezetimibe resulted in an MD in LDL-C of - 14.71% (95% CrI - 16.46, - 12.95) compared to doubling the starting dose of atorvastatin. The addition of ezetimibe to rosuvastatin resulted in an MD in LDL-C of - 14.96% (95% CrI - 17.79, - 12.11), compared to doubling the starting rosuvastatin dose. Similar trends were observed for changes in total cholesterol. IMPLICATIONS: Given the available data, the addition of ezetimibe to ongoing simvastatin, atorvastatin, or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose.

Quantitative Matching of Clutch Size in Reciprocating Hermaphroditic Worms.

Reciprocity [1] is one of the most controversial evolutionary explanations of cooperation among non-kin [2, 3]. For some authors, cognitive capacity of non-human organisms is limiting, and more parsimonious mechanisms should apply [3-5]; for others, the debate is mainly semantic [2, 6], and empirical evidence can be found in a wide range of taxa [7]. However, while the ability to alternate cooperative behaviors does not settle the reciprocity controversy, the capacity to adjust cooperative behavior to the value of received help could prove decisive. Marine polychaete worms Ophryotrocha diadema, as several simultaneous hermaphrodites, do not self-fertilize and have unilateral mating (i.e., they behave either as females or as males during each mating event). They are also external fertilizers and thus cannot store allosperm, which contribute to make them ideal model organisms to investigate reciprocity, since partners usually alternate sexual roles with each other, repeatedly exchanging egg clutch of variable size [8-12]. However, whether the alternation of sexual roles is the result of conditional reciprocity rather than by-product reciprocity has never been tested [13]. Here, we show that O. diadema worms reciprocate eggs conditionally to the partner's behavior and adjust the quality of cooperation according to that of their partners. Moreover, only egg reciprocation offers similar fitness returns via both the female and the male function with respect to non-reciprocating laying strategies. These results document that fine-tuned forms of conditional reciprocity can emerge in cognitively unsophisticated animals, broadening the criteria to recognize conditional reciprocity among animals.

Immunological alterations in frail older adults: A cross sectional study.

Frailty is a progressive physiologic decline in multiple body systems, characterized by loss of function, loss of physiologic reserve, and increased vulnerability to disease and death. This condition is induced by a complex and multifactorial interaction between genetic, biological, physical, psychological and environmental factors. To understand the interplay between the age-related decline of the immune response, and the upregulation of the inflammatory response, the so called inflammaging, we investigated the role of different inflammatory mediators on frailty status in the elderly. The study was performed in a population of 180 older adults (≥65 years), who were classified according to Fried's frailty phenotype. Plasma concentrations of neopterin, tryptophan, kynurenine, phenylalanine, tyrosine as well as kynurenine/tryptophan (Kyn/Trp) and phenylalanine/tyrosine (Phe/Tyr) ratios were analyzed as immune stimulation biomarkers. In addition, nitrite and C-reactive protein levels were measured as indicators of nitric oxide production and acute inflammation, respectively. Significant increases in neopterin, C-reactive protein and Kyn/Trp ratio, and decreases in tryptophan and nitrite concentrations in frail individuals compared with non-frail group were found. Both Kyn/Trp and Phe/Tyr ratios were significantly and positively correlated with neopterin. A positive correlation between kynurenine and tryptophan was also observed. Four parameters, i.e., neopterin, tryptophan, nitrite and C-reactive protein, were found to be strongly related to frailty status, although only nitrite confirmed its role of predictor after multiple regression analysis, supporting its use as a potential biomarker of frailty. Further investigation is required to strengthen the consistence and reproducibility of these findings, and to establish this parameter as a clinical biomarker of frailty.

Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature.

Schizophrenia is a severe, chronic mental disorder. Schizophrenia is visualized as an accelerated cellular aging syndrome characterized by early onset of cardiovascular disease causing premature mortality. In human aging involves alterations in telomere length (TL). To investigate the presence of TL shortening in schizophrenia and psychiatric syndromes associated, this condition was studied in leukocytes (LTL) of a sample of patients suffering from schizophrenia and other psychotic disorders, and compared with a group of non-psychiatric controls. We explored the relationship between LTL and age, gender, and smoking habit with the aim to control whether these potential confounding factors may influence the rate of telomeres shortening. We also performed a new comprehensive meta-analysis including studies on LTL in schizophrenia patients compared to healthy subjects published in the last two years and the results of the present study. Our results suggest that a diagnosis of schizophrenia, more than gender, age, cigarette smoking or alcohol drinking, is the most important condition responsible of the LTL shortening. A strong LTL shortening was observed in patients affected by schizophrenia, Schizoaffective disorder, and Psychosis not otherwise specified when they were younger than 50 years, while in the group of older subjects no major differences were observed. Additional evidence supporting the causal link of schizophrenia with accelerated telomeres shortening came from the analysis of the updated meta-analysis. The availability of a personalized profile of mechanistic pathways, risk factors, and clinical features may pose the basis for a rehabilitative treatment addressing individual needs of the psychiatric patients.

A review of telomere length in sarcopenia and frailty.

Sarcopenia and frailty are associated with several important health-related adverse events, including disability, loss of independence, institutionalization and mortality. Sarcopenia can be considered a biological substrate of frailty, and the prevalence of both these conditions progressively increases with age. Telomeres are nucleoprotein structures located at the end of linear chromosomes and implicated in cellular ageing, shorten with age, and are associated with various age-related diseases. In addition, telomere length (TL) is widely considered a molecular/cellular hallmark of the ageing process. This narrative review summarizes the knowledge about telomeres and analyzes for the first time a possible association of TL with sarcopenia and frailty. The overview provided by the present review suggests that leukocyte TL as single measurement, calculated by quantitative real-time polymerase chain reaction (qRT-PCR), cannot be considered a meaningful biological marker for complex, multidimensional age-related conditions, such as sarcopenia and frailty. Panels of biomarkers, including TL, may provide more accurate assessment and prediction of outcomes in these geriatric syndromes in elderly people.

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes.

BACKGROUND: We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 µg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. METHODS: The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. RESULTS: From the ITC, decreases in HbA1c were -1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20µg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. CONCLUSIONS: The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 µg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving.

Nest signature changes throughout colony cycle and after social parasite invasion in social wasps.

Social insects recognize their nestmates by means of a cuticular hydrocarbon signature shared by colony members, but how nest signature changes across time has been rarely tested in longitudinal studies and in the field. In social wasps, the chemical signature is also deposited on the nest surface, where it is used by newly emerged wasps as a reference to learn their colony odor. Here, we investigate the temporal variations of the chemical signature that wasps have deposited on their nests. We followed the fate of the colonies of the social paper wasp Polistes biglumis in their natural environment from colony foundation to decline. Because some colonies were invaded by the social parasite Polistes atrimandibularis, we also tested the effects of social parasites on the nest signature. We observed that, as the season progresses, the nest signature changed; the overall abundance of hydrocarbons as well as the proportion of longer-chain and branched hydrocarbons increased. Where present, social parasites altered the host-nest signature qualitatively (adding parasite-specific alkenes) and quantitatively (by interfering with the increase in overall hydrocarbon abundance). Our results show that 1) colony odor is highly dynamic both in colonies controlled by legitimate foundresses and in those controlled by social parasites; 2) emerged offspring contribute little to colony signature, if at all, in comparison to foundresses; and 3) social parasites, that later mimic host signature, initially mark host nests with species-specific hydrocarbons. This study implies that important updating of the neural template used in nestmate recognition should occur in social insects.