Evaluation of clinical practice guideline-derived clinical decision support systems using a novel quality model.

Over the last decade, clinical practice guidelines (CPGs) have become an important asset for daily life in healthcare organizations. Efficient management and digitization of CPGs help achieve organizational objectives and improve patient care and healthcare quality by reducing variability. However, digitizing CPGs is a difficult, complex task because they are usually expressed as text, and this often leads to the development of partial software solutions. At present, different research proposals and CPG-derived CDSS (clinical decision support system) do exist for managing CPG digitalization lifecycles (from modeling to deployment and execution), but they do not all provide full lifecycle support, making it more difficult to choose solutions or proposals that fully meet the needs of a healthcare organization. This paper proposes a method based on quality models to uniformly compare and evaluate technological tools, providing a rigorous method that uses qualitative and quantitative analysis of technological aspects. In addition, this paper also presents how this method has been instantiated to evaluate and compare CPG-derived CDSS by highlighting each phase of the CPG digitization lifecycle. Finally, discussion and analysis of currently available tools are presented, identifying gaps and limitations.

Chemotherapy safe handling practices in Ethiopia: A comprehensive multi-center evaluation.

INTRODUCTION: The increasing incidence of cancer and capacity for cancer care in Ethiopia has led to an upsurge in chemotherapy use in the country; however, studies indicate that there is a gap in the safe handling of chemotherapy by healthcare workers. There exists a need to understand if such unsafe practices occur in Ethiopia and, if so, which areas along the chemotherapy life cycle need the most improvement. METHODS: This study utilized a multi-method design through an online survey administered to health care professionals and evaluative site visits of eight cancer units in Addis Ababa, Ethiopia to understand the current conditions of chemotherapy handling. In addition, a survey was conducted among Ethiopian health care professionals from across the country. RESULTS: Fifty-five percent of survey participants disagreed or strongly disagreed that there are systems in place to identify, prevent, and address chemotherapy hazards in their workplace, and 71% of respondents denied having an active and effective health and safety committee and/or worker health and safety representative where they work. At evaluative site visits, only 30% of health care workers met the minimum guidelines for proper hand hygiene, and 20% of health care workers used adequate Personal Protective Equipment according to guidelines across the chemotherapy lifecycle. CONCLUSIONS: Results of this study indicate an urgent need for implementation of evidence-based interventions to improve chemotherapy handling in Ethiopia so that all patients and health care workers are protected from the hazardous toxicities of these drugs.

Metabolic Performance and Fate of Electrons during Nitrate-Reducing Fe(II) Oxidation by the Autotrophic Enrichment Culture KS Grown at Different Initial Fe/N Ratios.

Autotrophic nitrate-reducing Fe(II)-oxidizing (NRFeOx) microorganisms fix CO2 and oxidize Fe(II) coupled to denitrification, influencing carbon, iron, and nitrogen cycles in pH-neutral, anoxic environments. However, the distribution of electrons from Fe(II) oxidation to either biomass production (CO2 fixation) or energy generation (nitrate reduction) in autotrophic NRFeOx microorganisms has not been quantified. We therefore cultivated the autotrophic NRFeOx culture KS at different initial Fe/N ratios, followed geochemical parameters, identified minerals, analyzed N isotopes, and applied numerical modeling. We found that at all initial Fe/N ratios, the ratios of Fe(II)oxidized to nitratereduced were slightly higher (5.11 to 5.94 at Fe/N ratios of 10:1 and 10:0.5) or lower (4.27 to 4.59 at Fe/N ratios of 10:4, 10:2, 5:2, and 5:1) than the theoretical ratio for 100% Fe(II) oxidation being coupled to nitrate reduction (5:1). The main N denitrification product was N2O (71.88 to 96.29% at Fe/15N ratios of 10:4 and 5:1; 43.13 to 66.26% at an Fe/15N ratio of 10:1), implying that denitrification during NRFeOx was incomplete in culture KS. Based on the reaction model, on average 12% of electrons from Fe(II) oxidation were used for CO2 fixation while 88% of electrons were used for reduction of NO3- to N2O at Fe/N ratios of 10:4, 10:2, 5:2, and 5:1. With 10 mM Fe(II) (and 4, 2, 1, or 0.5 mM nitrate), most cells were closely associated with and partially encrusted by the Fe(III) (oxyhydr)oxide minerals, whereas at 5 mM Fe(II), most cells were free of cell surface mineral precipitates. The genus Gallionella (>80%) dominated culture KS regardless of the initial Fe/N ratios. Our results showed that Fe/N ratios play a key role in regulating N2O emissions, for distributing electrons between nitrate reduction and CO2 fixation, and for the degree of cell-mineral interactions in the autotrophic NRFeOx culture KS. IMPORTANCE Autotrophic NRFeOx microorganisms that oxidize Fe(II), reduce nitrate, and produce biomass play a key role in carbon, iron, and nitrogen cycles in pH-neutral, anoxic environments. Electrons from Fe(II) oxidation are used for the reduction of both carbon dioxide and nitrate. However, the question is how many electrons go into biomass production versus energy generation during autotrophic growth. Here, we demonstrated that in the autotrophic NRFeOx culture KS cultivated at Fe/N ratios of 10:4, 10:2, 5:2, and 5:1, ca. 12% of electrons went into biomass formation, while 88% of electrons were used for reduction of NO3- to N2O. Isotope analysis also showed that denitrification during NRFeOx was incomplete in culture KS and the main N denitrification product was N2O. Therefore, most electrons stemming from Fe(II) oxidation seemed to be used for N2O formation in culture KS. This is environmentally important for the greenhouse gas budget.

Platelets modulate CD4+ T-cell function in COVID-19 through a PD-L1 dependent mechanism.

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4+ T-cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T-cell dysfunction in COVID-19. We observed a high frequency of CD4+ T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)-α production by CD4+ T cells. In addition, interferon (IFN)-γ production was increased by platelets from HD but not from COVID-19 inpatients. A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD-L1-blocking antibody significantly restored platelets' ability to stimulate IFN-γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.

Sustained low-density lipoprotein-cholesterol <70 mg/dl is associated with improved cardiovascular outcomes in the clinical setting.

BACKGROUND AND AIMS: Clinical trials have shown that intensive low-density lipoprotein cholesterol (LDL-C) lowering improves cardiovascular outcomes among patients with atherosclerotic cardiovascular disease (ASCVD), but data are limited in real clinical practice, particularly for patients with ASCVD informing different territories. METHODS: FRENA was a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We compared the incidence of recurrent events in patients with sustained LDL-C levels <70 mg/dl compared with those with ≥70 mg/dl. RESULTS: As of December 2018, 1182 patients were eligible for this study. Among them, 172 (14.5%) had mean LDL-C levels ≤70 mg/dl, and 1010 (85.5%) had <70 mg/dl. Their clinical characteristics at baseline were similar. During 5 years of follow-up, 252 patients (21%) suffered major adverse cardiovascular events (MACE). The incidence rates of MACE were 3.42 events per 100 patient-years (95% confidence interval [95% CI] 2.17-5.14) in patients with levels <70 mg/dl and 5.57 (95% CI, 4.87-6.34) in those with ≥70 mg/dl; the rate ratio was 0.61 (95% CI, 0.39-0.92), p = 0.019. On multivariable analysis, patients with LDL-C levels <70 mg/dl were at lower risk for MACE (hazard ratio [HR]: 0.61 [95% CI, 0.39-0.93] p < 0.05). MACE reduction was driven by a decrease in coronary and peripheral events with no significant effect on stroke. CONCLUSIONS: Long-term sustained LDL-C <70 mg/dl in the clinical practice is associated with reduction in cardiovascular and peripheral vascular events with no apparent effect on stroke.

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment.

Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) have already been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages are also involved, and where the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement and ECM related genes (mainly CFH and ARMS2/HTRA1). Thus, carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully find a future cure. This necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems.

Location of recurrent cardiovascular events and anticardiolipin antibodies.

BACKGROUND: The relationship between anticardiolipin (aCL) antibodies and cardiovascular events is uncertain and may vary according to arterial location. MATERIALS AND METHODS: FRENA is an ongoing registry of stable outpatients with symptomatic coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral artery disease (PAD). The rate of subsequent ischaemic events was cross-referenced with the presence of aCL antibodies (any isotype, IgG or IgM). RESULTS: As of June 2017, 1387 stable outpatients were recruited. Of these, 120 (8.7%) showed positive levels of aCL antibodies. Over an average follow-up of 18 months, 250 patients developed subsequent events: 101 myocardial infarction, 57 ischaemic stroke and 92 critical leg events. Patients with positive aCL antibodies had a higher risk of distal artery events (a composite of ischaemic stroke or critical leg events) than patients with undetectable or low levels (rate ratio: 1.66; 95% CI: 1.07-2.60). However, an association with central coronary events was not found. The multivariate Cox analysis after adjustment for relevant clinical covariates showed that positivity of aCL antibodies is an independent risk factor for distal events (hazard ratio: 1.60; 95% CI: 1.01-2.55; P < .05). CONCLUSIONS: Positivity of aCL antibodies is associated with an increased risk of subsequent distal artery ischaemic events (cerebral or leg arteries) but not coronary artery events. Anticardiolipin antibodies appear to have a different relationship on the localisation of ischaemic events in patients with symptomatic artery disease.

Right ventricular resynchronization in a patient with repaired tetralogy of Fallot and severe ventricular dysfunction.

Right ventricular (RV) resynchronization therapy (CRT) with stimulation electrode implantation in the latest activation area guided by a high-density electroanatomic activation map was successfully performed in a patient with repaired tetralogy of Fallot (rToF), severe pulmonary regurgitation (PR), and severe dysfunction and dilatation of the right ventricle. An improvement in his clinical condition and intraventricular synchrony was achieved. There is a mechanical-electrical interaction in the right ventricle of patients with rToF; therefore, RV CRT in selected cases may be beneficial. Electroanatomic activation mapping can help achieve maximum clinical benefit by identifying the optimal stimulation site.

Effectiveness of a brief motivational intervention to increase the breastfeeding duration in the first 6 months postpartum: Randomized controlled trial.

AIMS: To evaluate the effectiveness of a brief motivational intervention to increase the breastfeeding duration in the first 6 months postpartum in mothers who began breastfeeding in the first hour after birth and to explore the role of general and breastfeeding self-efficacy in this relationship. DESIGN: A multi-centre randomized controlled clinical trial. METHODS: Data were collected from February 2018 - March 2019. Women were randomly assigned to an intervention group that received a brief motivational intervention (N = 44) or a control group that was offered standard education on breastfeeding (N = 44). Survival analysis techniques were carried out with a follow-up of 6 months. In addition, the roles of breastfeeding and general self-efficacy in the association between BMI and breastfeeding duration were explored through mediation/moderation analysis. RESULTS: Among 88 randomized patients (mean age, 32.82 years), 81 (92.04%) completed the trial. The survival analyses of exclusive breastfeeding and breastfeeding (exclusive and non-exclusive) showed reductions in the risk of abandonment in the intervention group of 63% (aHR: 0.37 [0.22-0.60] p < .001) and 61% (aHR: 0.39 [0.20-0.78] p = .008), respectively. We found that self-efficacy acted as a moderator of the effect of brief motivational intervention on breastfeeding self-efficacy. A discrete indirect effect of brief motivational intervention through increased breastfeeding self-efficacy was found on breastfeeding duration, with an index of moderated mediation of 0.08 (95% CI: 0.02-0.19). Greater positive variations in the breastfeeding self-efficacy scores during follow-up predicted exclusive and non-exclusive breastfeeding duration. CONCLUSION: A brief motivational intervention conducted in the immediate postpartum period increases breastfeeding and exclusive breastfeeding duration in the first 6 months. Although breastfeeding self-efficacy seems to moderate the effect of brief motivational intervention on the increase in breastfeeding duration, other factors may influence its effectiveness. Further studies could focus on exploring how brief motivational intervention works and whether it also works for pregnant mothers who have not yet decided whether to breastfeed. IMPACT: Brief motivational intervention could be introduced as part of routine care of women who begin breastfeeding to improve the low rates of exclusive breastfeeding at 6 months postpartum. TRIAL REGISTRATION: Unique Protocol ID: Moti003; https://ClinicalTrials.gov ID: NCT03357549.

A randomized controlled trial to evaluate the effectiveness of a brief motivational intervention to improve exclusive breastfeeding rates: Study protocol.

AIMS: To estimate the effectiveness of a brief motivational intervention (BMI) in increasing the duration of exclusive breastfeeding in the first 6 months postpartum. A complementary aim was to examine a potential mediating role of breastfeeding self-efficacy in the effectiveness of the BMI. BACKGROUND: Breastfeeding is associated with benefits for babies and mothers' health. Among the pool of techniques used to encourage healthy behaviours, BMI is highlighted based on the principles of motivational interviewing. One of the main components of these interventions is the promotion of self-efficacy, which, in fact, is a key factor for breastfeeding success. DESIGN: A multi-centre randomized controlled clinical trial of parallel groups. METHODS: Women who begin to breastfeed in the first hour after birth will be randomly assigned to the intervention group (receiving a BMI at immediate postpartum plus a telephone booster at the 1st and 3rd month postpartum) or the control group (receiving standard breastfeeding education at the same time). Outcome measures include the following: breastfeeding, breastfeeding self-efficacy, general self-efficacy, and postnatal depression. Data will be collected before the intervention and at the 1st, 3rd, and 6th month after birth. The study protocol has been approved by Badajoz Ethics Committee of Clinical Research in October 2017. DISCUSSION: This study will identify the effectiveness of BMI in improving exclusive breastfeeding rates. The findings will give useful evidence to health professionals about how to support breastfeeding. IMPACT: This study will address the low-exclusive breastfeeding rates, that in our country are far lower than World Health Organization's recommendation.

A Symphony of Signals: Intercellular and Intracellular Signaling Mechanisms Underlying Circadian Timekeeping in Mice and Flies.

The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator network in which individual cellular oscillators are tightly coupled to the environmental day-night cycle, and to one another via intercellular coupling. In this review, we will summarize the roles of various neurotransmitters and neuropeptides in the regulation of circadian entrainment and synchrony within the mammalian and Drosophila central pacemakers. We will also describe the diverse functions of protein kinases in the relay of input signals to the core oscillator or the direct regulation of the molecular clock machinery.

Microencapsulated food-grade antioxidant applied as a preservative of peanut seed quality in microcosm- and pilot-scale trials.

BACKGROUND: In Argentina, peanuts are stored for 3-6 months. It is important to avoid proliferation of fungi and insect pests during this period. In this study, the potential of butylated hydroxyanisole (BHA) microcapsules to conserve peanut kernels was evaluated in microcosms and on a pilot scale. RESULTS: In microcosm assays, microcapsules containing BHA at a dose of 1802 µg g-1 reduced 37% of total fungal count. Higher reductions (77-100%) were obtained with a combined treatment with BHA formulation (1802 µg g-1 ) plus fungicide (methyl thiophanate 0.0100 g L-1  and metalaxyl 0.0133 g L-1 ). However, germination levels of peanut seeds treated with the BHA formulation were less than 6% throughout the incubation time. In pilot-scale trials, the storage conditions allowed the control of fungal development and insect proliferation. Quantifiable levels of BHA were also detected throughout the entire storage period. The combined treatment significantly reduced fungal contamination at 2 months of storage (C1-2015: 37.41%; C1-2016: 28.48%; C2-2016: 45.02%). Seed germination of unshelled stored peanuts was not affected by the formulation. CONCLUSION: The application of the BHA formulation during storage combined with pre-seeding treatment could be an appropriate strategy to maintain the quality of the peanut kernels destined for seed. © 2018 Society of Chemical Industry.

Green beards and signaling: Why morality is not indispensable.

We argue that although objectivist moral attitudes may facilitate cooperation, they are not necessary for the high levels of cooperation in humans. This is implied by evolutionary models that articulate a mechanism underlying Stanford's account, and is also suggested by the ability of merely conventional social norms to explain extreme human behaviors.

Efficacy of epiphytic bacteria to prevent northern leaf blight caused by Exserohilum turcicum in maize.

Eight potential biological control agents (BCAs) were evaluated in planta in order to assess their effectiveness in reducing disease severity of northern leaf blight caused by Exserohilum turcicum. The assay was carried out in greenhouse. Twenty-six-day-old plants, V4 phenological stage, were inoculated with antagonists by foliar spray. Only one biocontrol agent was used per treatment. Ten days after this procedure, all treatments were inoculated with E. turcicum by foliar application. Treatments performed were: C-Et: control of E. turcicum; T1: isolate 1 (Enterococcus genus)+E. turcicum; T2: isolate 2 (Corynebacterium genus)+E. turcicum; T3: isolate 3 (Pantoea genus)+E. turcicum; T4: isolate 4 (Corynebacterium genus)+E. turcicum; T5: isolate 5 (Pantoea genus)+E. turcicum; T6: isolate 6 (Bacillus genus)+E. turcicum; T7: isolate 7 (Bacillus genus)+E. turcicum; T8: isolate 8 (Bacillus genus)+E. turcicum. Monitoring of antagonists on the phyllosphere was performed at different times. Furthermore, the percentage of infected leaves and, plant and leaf incidence were determined. Foliar application of different bacteria significantly reduced the leaf blight between 30-78% and 39-56% at 20 and 39 days respectively. It was observed that in the V10 stage of maize plants, isolate 8 (Bacillus spp.) caused the greatest effect on reducing the severity of northern leaf blight. Moreover, isolate 8 was the potential BCA that showed more stability in the phyllosphere. At 39 days, all potential biocontrol agents had a significant effect on controlling the disease caused by E. turcicum.

Effect of Photoperiod On Permethrin Resistance In Aedes aegypti.

Living organisms have been exposed to light-dark cycles that allowed them to adapt to different ecological niches. Circadian cycles affect hormone release, metabolism, and response to xenobiotic compounds. Current studies have shown that insect susceptibility to toxic agents depends on circadian cycles, mainly because the biochemical processes involved in detoxification and responses to oxidative stress are modulated by this process. The goal of this study was to determine the effect of photoperiod on resistance to permethrin in Aedes aegypti . Collections of Ae. aegypti from 4 locations in Yucatan, southern Mexico, were subjected to 2 different photoperiod schemes: dark (0 h light:24 h dark) and natural photoperiod (12 h light:12 h dark). The comparison of both photoperiods was evaluated with respect to permethrin resistance using bottle bioassays and by monitoring the possible mechanism related such as enzymatic activity and by the frequency of 2 knockdown resistance mutations in the voltage-dependent sodium channel gene (V1016I and F1534C). The susceptible strain was used as a reference. The mosquitoes in dark photoperiod showed a reduction in resistance to the pyrethroid. The α-esterases and glutathione S-transferase enzymatic activities showed lower levels in the dark photoperiod, and the frequencies of V1016I knockdown resistance mutation showed significant difference between photoperiod schemes.

Optimization of Experimental Parameters to Explore Small-Ligand/Aptamer Interactions through Use of (1) H†NMR Spectroscopy and Molecular Modeling.

Aptamers constitute an emerging class of molecules designed and selected to recognize any given target that ranges from small compounds to large biomolecules, and even cells. However, the underlying physicochemical principles that govern the ligand-binding process still have to be clarified. A major issue when dealing with short oligonucleotides is their intrinsic flexibility that renders their active conformation highly sensitive to experimental conditions. To overcome this problem and determine the best experimental parameters, an approach based on the design-of-experiments methodology has been developed. Here, the focus is on DNA aptamers that possess high specificity and affinity for small molecules, L-tyrosinamide, and adenosine monophosphate. Factors such as buffer, pH value, ionic strength, Mg(2+) -ion concentration, and ligand/aptamer ratio have been considered to find the optimal experimental conditions. It was then possible to gain new insight into the conformational features of the two ligands by using ligand-observed NMR spectroscopic techniques and molecular mechanics.

Modes of migration and multilevel selection in evolutionary multiplayer games.

The evolution of cooperation in group-structured populations has received much attention, but little is known about the effects of different modes of migration of individuals between groups. Here, we have incorporated four different modes of migration that differ in the degree of coordination among the individuals. For each mode of migration, we identify the set of multiplayer games in which the cooperative strategy has higher fixation probability than defection. The comparison shows that the set of games under which cooperation may evolve generally expands depending upon the degree of coordination among the migrating individuals. Weak altruism can evolve under all modes of individual migration, provided that the benefit to cost ratio is high enough. Strong altruism, however, evolves only if the mode of migration involves coordination of individual actions. Depending upon the migration frequency and degree of coordination among individuals, conditions that allow selection to work at the level of groups can be established.

Segmental fat-free and fat mass measurements by bioelectrical impedance analysis in 2,224 healthy Spanish women aged 18-85 years.

OBJECTIVES: This study provides updated data on body composition in adult Spanish women. METHODS: We considered data, including height and weight, from a survey conducted on a total of 4,013 adult women between 2009 and 2010. A subgroup of 2,224 women completed a bioelectrical body impedance analysis of body composition using a Tanita Body Composition Analyzer (Model no. BF-418). RESULTS: Total fat mass (FM) gradually increased between 18 and 74 years of age and decreased thereafter. FM increased in both legs between 65 and 74 years of age (5.69 ± 1.4 Kg and 5.66 ± 1.4 Kg for right and left legs, respectively) and decreased thereafter. FM in the right arm increased until 44 years of age (1.22 ± 2.6 Kg), decreased to 1.19 ± 0.5 Kg between 45 and 54 years of age, and increased to 1.54 ± 0.63 from 65 to 74 years of age. FM in the left arm increased constantly until it reached a peak of 1.63 ± 0.6 Kg between 65 and 74 years of age and decreased thereafter. FM increased in the trunk throughout life (peaks at 13.27±3.8 Kg) until subjects reached between 65 and 74 years of age. Fat free mass increased until 44 years of age (42.42 ± 4.17 Kg) and decreased thereafter. The prevalence of overweight/obesity significantly increased with age in the entire sample. CONCLUSIONS: Our results indicate that age-related increases in weight were at least partially due to increased adiposity.

Direct reciprocity in structured populations.

Reciprocity and repeated games have been at the center of attention when studying the evolution of human cooperation. Direct reciprocity is considered to be a powerful mechanism for the evolution of cooperation, and it is generally assumed that it can lead to high levels of cooperation. Here we explore an open-ended, infinite strategy space, where every strategy that can be encoded by a finite state automaton is a possible mutant. Surprisingly, we find that direct reciprocity alone does not lead to high levels of cooperation. Instead we observe perpetual oscillations between cooperation and defection, with defection being substantially more frequent than cooperation. The reason for this is that "indirect invasions" remove equilibrium strategies: every strategy has neutral mutants, which in turn can be invaded by other strategies. However, reciprocity is not the only way to promote cooperation. Another mechanism for the evolution of cooperation, which has received as much attention, is assortment because of population structure. Here we develop a theory that allows us to study the synergistic interaction between direct reciprocity and assortment. This framework is particularly well suited for understanding human interactions, which are typically repeated and occur in relatively fluid but not unstructured populations. We show that if repeated games are combined with only a small amount of assortment, then natural selection favors the behavior typically observed among humans: high levels of cooperation implemented using conditional strategies.

Evil green beards: Tag recognition can also be used to withhold cooperation in structured populations.

Natural selection works against cooperation unless a specific mechanism is at work. These mechanisms are typically studied in isolation. Here we look at the interaction between two such mechanisms: tag recognition and population structure. If cooperators can recognize each other, and only cooperate among themselves, then they can invade defectors. This is known as the green beard effect. Another mechanism is assortment caused by population structure. If interactions occur predominantly between alike individuals, then indiscriminate cooperation can evolve. Here we show that these two mechanisms interact in a non-trivial way. When assortment is low, tags lead to conventional green beard cycles with periods of tag based cooperation and periods of defection. However, if assortment is high, evil green beard cycles emerge. In those cycles, tags are not used to build up cooperation with others that share the tag, but to undermine cooperation with others that do not share the tag. High levels of assortment therefore do not lead to indiscriminate cooperation if tags are available. This shows that mechanisms that are known to promote cooperation in isolation can interact in counterintuitive ways.