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Abstract For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the 7,12-dimethylbenz[a]anthracene-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, surgical placement of fulvestrant-eluting implants was safe and did not elicit significant breast tissue pathology when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.

Abstract Background Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes. In an effort to expand the clinical use of PARP inhibitors to HRR proficient tumors, several groups have tested combinations of DNA methyltransferase inhibitors and PARP inhibitors. While this approach attenuated tumor cell proliferation in preclinical studies, subsequent clinical trials revealed little benefit. We hypothesized that benefit for this drug combination would only be specific to HRR deficient tumors, due to their inability to enact high fidelity DNA repair with subsequent cell death. Methods We generated hypomorphic BRCA1 and BRCA2 variants of the HRR proficient triple negative breast cancer cell line MDA-MB-231. We compared therapeutic response features such as RAD51 focus formation, cell cycle fraction alterations, DNA damage accumulation, colony formation, and cell death of these and other cell lines with and without intrinsic BRCA1/2 mutations. Results were confirmed in BRCA1/2 intact and deficient xenografts and PDX. Results Our targeted variants and cells with intrinsic BRCA1/2 mutations responded to low dose combination therapeutic treatment by G2M stalling, compounded DNA damage, severely attenuated colony formation, and importantly, increased cell death. In contrast, the parental MDA-MB-231 cells and other HRR proficient cell lines produced smaller cell populations with short term treatment, but with much less cumulative DNA damage, and minimal cell death. In animal studies, our BRCA-engineered hypomorphs and several independent PDX models with clinically relevant BRCA mutations were acutely more vulnerable to this drug combination. Conclusions We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities.

The Critical Power Model (CPM) is key for assessing athletes’ aerobic and anaerobic energy systems but typically involves lengthy, exhausting protocols. The 3 min all-out test (3MT) simplifies CPM assessment, yet its duration remains demanding. Exponential decay models, specifically mono- and bi-exponential functions, offer a more efficient alternative by accurately capturing the nonlinear energy dynamics in high-intensity efforts. This study explores shortening the 3MT using these functions to reduce athlete strain while preserving the accuracy of critical power (CP) and work capacity (W′) estimates. Seventy-six competitive cyclists and triathletes completed a 3MT on a cycle ergometer, with CP and W′ calculated at shorter intervals. Results showed that a 90 s test using the bi-exponential model yielded CP and W′ values similar to those of the full 3MT. Meanwhile, the mono-exponential model required at least 135 s. Bland–Altman and linear regression analyses confirmed that a 120 s test with the mono-exponential model reliably estimated CP and W′ with minimal physical strain. These findings support a shortened, less-demanding 3MT as a valid alternative for CPM assessment.

Background: The critical power model (CPM) is used extensively in sports to characterize fitness by estimating anaerobic work capacity (W’) and critical power (CP). Traditionally, estimates of CP and W’ require repeated, time-consuming tests. Alternatively, a 3 min all-out test yields good estimates of W’ and CP. However, adoption of the 3 min protocol for regular fitness monitoring is deterred by the mentally/physically strenuous nature of the test. Objective: We propose to examine an alternative single-session testing protocol that can accurately estimate critical power model parameters. Methods: Twenty-eight healthy competitive athletes (cyclists or triathletes) (mean ± SD: age: 38.5 ± 10.4 years, height: 177.9 ± 8.6 cm, mass: 73.4 ± 9.9 kg) participated in 5 sessions on a Lode cycle ergometer in isokinetic mode within a 2-week period. A 3 min all-out test (3MT) was conducted on the first visit to determine CPM parameters from which power outputs for 4 subsequent constant-power plus all-out tests (CPT) were selected to result in exhaustion in 1–10 min. The subjects were to maintain the prescribed power output as consistently as possible at their preferred race cadence. Once the power output could no longer be maintained for more than 10 s, the subjects were instructed to produce an all-out effort. Tests were terminated after power output fell to an asymptote which was sustained for 2 min. Results: The CPM parameters for all of the CPT durations were compared to the traditional CP protocol (significant parameter differences were identified for all CPT durations) and the 3MT (only CPT durations > 3 min were different [3–6 min test, p < 0.01; >6 min test, p < 0.01]). CPT does not estimate traditional CP and W’ parameters well. However, the CPT with a duration < 3 min accurately estimates both parameters of a 3MT. Conclusion: Therefore, CPT has the capacity to serve as an alternative tool to assess CP parameters.

Objectives: To investigate the effect of exercise intensity on functional capacity in individuals with coronary artery disease, assess adherence to the heart rate training zone (HRTZ), and determine the relationship between trained intensity and functional capacity. Methods: A retrospective study was conducted on the medical records of 54 outpatients with coronary artery disease in a public hospital. The prescribed intensity started at 50%–60% of the heart rate reserve, increasing monthly to 70%–80% by the third month. Spearman’s test was used to assess the correlation between improvement in distance in the incremental shuttle walk test (ISWT), exercise intensity, and rating of perceived exertion (Borg–RPE). Adherence was classified as ‘below’ when HRTZ was not achieved in any phase of the program, ‘intermediate’ when HR was within the HRTZ for one or two months, and ‘above’ when HR was at or higher than HRTZ ≥ two months. Improvement was tested using t-test and one-way ANOVA. Results: 51.9% of participants had an increase in ISWT of ≥70 m (p < 0.0001). In at least one month, 50.9% trained below HRTZ. The trained intensity did not fall below 8.6% of the prescribed HRTZ minimum threshold. Changes in ISWT were not significantly correlated with exercise intensity (p = 0.87) or Borg–RPE (p = 0.16). Conclusion: While a significant increase in functional capacity was found, considerable heterogeneity in changes were observed. This may, in part, be related to adherence to HRTZ with progressive exercise intensity and to the variability in exercise volume in cardiovascular rehabilitation programs.

Abstract Predisposition to autoimmunity and inflammatory disorders is observed in patients with fragile X-associated syndromes. These patients have increased numbers of CGG triplets in the 5’ UTR region of FMR1 (Fragile X Mental Retardation 1) gene, that affects its expression. FMR1 is decreased in the thymus of myasthenia gravis (MG) patients, a prototypical autoimmune disease. We thus analyzed the number of CGG triplets in FMR1 in MG, and explored the regulatory mechanisms affecting thymic FMR1 expression. We measured the number of CGGs using thymic DNA from MG and controls, but no abnormalities in CGGs were found in MG that could explain thymic decrease of FMR1. We next analyzed by RT-PCR the expression of FMR1 and its transcription factors in thymic samples, and in thymic epithelial cell cultures in response to inflammatory stimuli. In control thymuses, FMR1 expression was higher in males than females, and correlated with CTCF (CCCTC-binding factor) expression. In MG thymuses, decreased expression of FMR1 was correlated with both CTCF and MAX (Myc-associated factor X) expression. Changes in FMR1 expression were supported by western blot analyses for FMRP. In addition, we demonstrated that FMR1, CTCF and MAX expression in thymic epithelial cells was also sensitive to inflammatory signals. Our results suggest that FMR1 could play a central role in the thymus and autoimmunity. First, in relation with the higher susceptibility of females to autoimmune diseases. Second, due to the modulation of its expression by inflammatory signals that are known to be altered in MG thymuses.

Globally over 2 million women are diagnosed with breast cancer each year despite major advances in detection and treatment of the disease. Breast cancer is comprised of several distinct subtypes and understanding the heterogeneity of the disease has become crucial for treatment planning. Therapeutic strategies span from a hormone therapy-based focus for women with estrogen receptor positive breast cancer to targeting human epidermal growth factor (HER2) by small molecules, antibody-drug-conjugates (ADC) and monoclonal antibodies in those with HER2 overexpression. Other novel treatment strategies for select subgroups of patients include the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors for women with estrogen receptor positive tumors, the poly ADP ribose polymerase (PARP) inhibitors for those with BRCA mutations, and phosphoinositide 3-kinase (PI3K) inhibitors for women with tumors harboring phophatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit alpha (PIK3CA) mutations. In contrast, the treatment for women with triple negative breast cancer has until recently been solely limited to chemotherapy. The profound impact of immunotherapy on cancer treatment in general has created much hope for its potential in breast cancer. This review will focus on the current advances and the research of immunotherapy in breast cancer, particularly on immune checkpoint inhibitors, adoptive cell transfer and cancer vaccines.

Mesothelioma in situ is a recently described precursor to invasive mesothelioma. Thus far, all cases in the literature have involved one pleural cavity or the peritoneal cavity. We describe a patient with biopsy-proven mesothelioma in situ involving both pleural cavities and the peritoneal cavity. Genetic analysis results revealed that the patient had a BAP1 germline mutation. This is the first report of mesothelioma in situ involving multiple body cavities and raises a question of whether such patients will all have BAP1 germline mutations.

Abstract A primary goal of a future e + e − collider program will be the precision measurement of Higgs boson properties. For practical reasons it is of interest to determine the minimal set of detector specifications required to reach this and other scientific goals. Here we investigate the precision obtainable for the e + e − → Zh → μ + μ − X inclusive cross section and the Higgs boson mass using the di-muon recoil method, considering a detector that has only an inner tracking system within a solenoidal magnetic field, surrounded by many nuclear interaction lengths of absorbing material, and an outer muon identification system. We find that the sensitivity achievable in these measurements with such a tracking detector is only marginally reduced compared to that expected for a general purpose detector with additional electromagnetic and hadronic calorimeter systems. The difference results mainly from multi-photon backgrounds that are not as easily rejected with tracking detectors. We also comment on the prospects for an analogous measurement of the e + e − → Zh → e + e − X inclusive cross section. Finally, we study searches for light scalars utilizing the di-muon recoil method, estimating the projected reach with a tracking or general purpose detector.

ER-positive breast cancer patients do not usually respond to immunotherapy. In this phase II clinical trial, the authors report the safety and efficacy of combining vorinostat and pembrolizumab with tamoxifen in ER-positive breast cancers and provide evidence that T-cell exhaustion may serve as a potential signature for the response of this combination therapy.

Background: Although patient education is considered a core component of cardiac rehabilitation (CR) programs, to our knowledge, no educational program designed for CR has been standardized in Canada. This absence of standardization may be due to a lack of reliable resources to educate these patients. The objective of this study was to assess the effectiveness of an education intervention in improving knowledge and health behaviours among CR patients in 3 sites in Canada. Methods: CR patients were exposed to an evidence- and theoretically based comprehensive education intervention. Patients completed surveys assessing knowledge, physical activity, food intake, self-efficacy, and health literacy. All outcomes were assessed pre- and post-CR. Paired t tests were used to investigate variable changes between pre- and post-CR, Pearson correlation coefficients were used to determine the association between knowledge and behaviours, and linear regression models were computed to investigate differences in overall post-CR knowledge based on participant characteristics. Results: A total of 252 patients consented to participate, of whom 158 (63.0%) completed post-CR assessments. There was a significant improvement in patients’ overall knowledge pre- to post-CR, as well as in exercise, food intake, and self-efficacy (P < 0.05). Results showed a significant positive correlation between post-CR knowledge and food intake (r = 0.203; P = 0.01), self-efficacy (r = 0.201; P = 0.01), and health literacy (r = 0.241; P = 0.002). Education level (unstandardized beta = −2.511; P = 0.04) and pre-CR knowledge (unstandardized beta = 0.433; P < 0.001) were influential in changing post-CR knowledge. Conclusion: In this first-ever multi-site study focusing on patient education for CR patients in Canada, the benefits of an education intervention have been supported. Résumé: Contexte: Bien que l’éducation du patient soit considérée comme un élément essentiel des programmes de réadaptation cardiaque (RC), il n’existe, à notre connaissance, aucun programme éducatif standardisé en RC au Canada. Cette absence de standardisation peut être attribuable à un manque de ressources fiables en matière d’éducation des patients. Cette étude visait à évaluer l’efficacité réelle d’une intervention éducative au regard de l’amélioration des connaissances et des comportements touchant la santé chez des patients en RC dans trois établissements au Canada. Méthodologie: Une intervention éducative globale fondée sur des données probantes et théoriques a été menée auprès de patients en RC. Les patients ont répondu à des questionnaires d’évaluation des connaissances, de l’activité physique, de l’apport alimentaire, de l’autoefficacité et de la littératie en matière de santé. Tous les résultats ont été évalués avant et après la RC. Des tests t pour échantillons appariés ont été utilisés pour étudier les changements touchant les variables évaluées avant et après la RC, des coefficients de corrélation de Pearson ont servi à déterminer l’association entre les connaissances et les comportements, et des modèles de régression linéaire ont été calculés pour étudier les différences dans les connaissances globales après la RC en fonction des caractéristiques des participants. Résultats: Au total, 252 patients ont accepté de participer; de ce nombre, 158 (63,0 %) ont pris part aux évaluations postérieures à la RC. Les connaissances globales des patients se sont améliorées de façon significative d’avant à après la RC, tout comme l’activité physique, l’apport alimentaire et l’autoefficacité (p < 0,05). Les résultats ont montré une corrélation positive significative entre les connaissances et l’apport alimentaire (r = 0,203; p = 0,01), l’autoefficacité (r = 0,201; p = 0,01) et la littératie en matière de santé (r = 0,241; p = 0,002) après la RC. Le niveau d’éducation (B = -2,511; p = 0,04) et les connaissances avant la RC (B = 0,433; p < 0,001) ont influé sur les changements touchant les connaissances après la RC. Conclusion: Cette toute première étude multicentrique axée sur l’éducation des patients en RC au Canada a permis de confirmer les avantages d’une intervention éducative.

BackgroundMusic performance anxiety is a common experience among elite and professional musicians and impedes performers from achieving flow state, or a state of focused, sustained engagement that promotes optimal performance.ObjectiveThe aim of this study was to use heart rate variability (HRV) to determine the psychophysiological underpinnings of optimal music performance.MethodsWe assessed HRV to study how autonomic-cardiac modulation was associated with flow during piano performance. Twenty-two pianists (15–22 years) with at least a Grade 8 Royal Conservatory of Music certification prepared two standardized pieces and a self-selected piece. Performer heart rate data were measured with a Polar 800 watch in 5-min periods immediately before performances, during performances and post-performance. HRV was employed to assess autonomic modulation of cardiac intervals. HRV indices of sympathetic and parasympathetic modulation of the heart were analyzed in 2.5-min segments to monitor short-term autonomic adjustments using the Kubios HRV Software. Flow state was measured using the 36-item Flow State Scale (FSS). Relationships were analyzed using zero-order correlations and multiple linear regressions.ResultsOur sample consisted of 22 RCM Grade 8 certified pianists. Participants achieved the highest level of flow during performance of the Bach piece. Decreased HRV was observed during performance, as indicated by a significant drop in total power. Flow state was positively associated with High Frequency (HF) power during the pre-performance phase, and inversely associated with Low Frequency (LF) power during performance.ConclusionInverse association of flow with LF-HRV during performance affirms the importance of vagal-HR modulation for achievement of flow state. Increased HF-HRV and reduced LF-HRV immediately prior to performance suggests that flow state may be shaped as much by physiological preparation during pre-performance as it is by physiologic responses during performance. Further research is required to validate the correlation between autonomic modulation of the heart and flow state. Evidence of this correlation between autonomic modulation of the heart and achievement of flow state may pave the way for further research on enhancing musical performance and targeting MPA through HRV-based interventions.

No abstract available.

Abstract Background Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. Methods MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). Results Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P

Direct transmission of bacteria to subsequent generations highlights the beneficial nature of host-bacteria relationships. In insects, this process is often mediated by the production of microbe-containing secretions. The objective of this study was to determine if the burying beetle, Nicrophorus defodiens, utilizes anal secretions to transmit adult digestive tract bacteria onto a small vertebrate carcass; thus creating the potential to aid in carcass preservation or pass digestive tract bacteria to their larval offspring. Using high-throughput Illumina sequencing of the 16S rRNA gene, we characterized bacterial communities of adult beetle digestive tracts, their anal secretions, and prepared mouse carcasses. We also examined unprepared carcass bacterial communities as a means to interpret community shifts that take place during carcass preservation. We found a vast reduction in diversity on prepared carcasses after anal secretion application. Overall, there was little similarity in bacterial communities among adult digestive tracts, anal secretions, and prepared carcasses, suggesting bacterial communities found in adult digestive tracts do not successfully colonize and achieve dominance on prepared carcasses by way of beetle anal secretions. We concluded that N. defodiens does not transmit their digestive tract bacterial communities to prepared carcasses in a wholesale manner, but may transmit key microbes, including core microbiome members, to preserved carcasses that may ultimately act to sustain larvae and serve as inocula for larval digestive tracts.

Currently, demand for US-bred and born detector dogs exceeds available supply, while reliance on foreign-bred sources introduces many unnecessary and unwanted risks. With proper management of a domestic supply line, U.S. breeders can improve both health and behavior by applying scientific principles to breeding and raising of detector dogs. A cooperative national detector dog breeding and development program will mitigate the current shortage of domestic-bred dogs that meet the health and behavior standards required by government, military, and law enforcement agencies. To coordinate such a cooperative, we propose a Detector Dog Center of Excellence (DDCoE) led by representatives of academic canine science programs guided by an advisory board of stakeholders. As a non-governmental organization, the DDCoE will oversee selective breeding of dogs owned by breeders, purchase the resulting puppies, and its members will supervise puppy raising until dogs are of a suitable age to be purchased by government agencies or other working dog organizations. The DDCoE will serve as an approved vendor to facilitate the procurement process. Breeding decisions will be based on proven quantitative genetic methods implemented by a specialized database. A national working dog semen bank will ensure conservation of diverse genetic material and enhance selection response by providing numerous potential sires. As a data collection and genetic evaluation center, the DDCoE will lead research to define quantitative traits involved in odor detection, to understand how these traits develop, and methods to optimize training of dogs endowed with enhanced odor detection ability.

Cooperation is prevalent across bacteria, but risks being exploited by non-cooperative cheats. Horizontal gene transfer, particularly via plasmids, has been suggested as a mechanism to stabilize cooperation. A key prediction of this hypothesis is that genes which are more likely to be transferred, such as those on plasmids, should be more likely to code for cooperative traits. Testing this prediction requires identifying all genes for cooperation in bacterial genomes. However, previous studies used a method which likely misses some of these genes for cooperation. To solve this, we used a new genomics tool, SOCfinder, which uses three distinct modules to identify all kinds of genes for cooperation. We compared where these genes were located across 4648 genomes from 146 bacterial species. In contrast to the prediction of the hypothesis, we found no evidence that plasmid genes are more likely to code for cooperative traits. Instead, we found the opposite-that genes for cooperation were more likely to be carried on chromosomes. Overall, the vast majority of genes for cooperation are not located on plasmids, suggesting that the more general mechanism of kin selection is sufficient to explain the prevalence of cooperation across bacteria.

BackgroundHeart rate variability (HRV) is a non-invasive neurophysiological measure of autonomic nervous system regulation emerging in concussion research. To date, most concussion studies have focused on the university-aged athlete with no research examining healthy active youths. Corroborating changes in HRV alongside traditional subjective self-report measures (concussion symptoms) in the non-concussed state provides a foundation for interpreting change following concussion. The objectives were to (1) explore the influence of age and sex on HRV and (2) examine the relationship between HRV and baseline/pre-injury concussion symptom domains (physical, cognitive, emotional, and fatigue) in healthy youth athletes.MethodHealthy, youth athletes 13–18 years of age [N = 294, female = 166 (56.5%), male = 128 (43.5%)] participated in this cross-sectional study. Age, sex, and concussion-like symptoms were collected as part of a baseline/pre-injury assessment. The Post-Concussion Symptom Inventory-SR13 (PCSI-SR13) was used to collect domain scores for physical, cognitive, emotional, and fatigue symptoms. HRV was collected for 24 h. HRV measures included time (SDNN, RMSSD, and pNN50) and frequency (HF, HFnu, LF, LFnu, and total power) domain HRV measures. Variables were logarithmically transformed to increase robustness of linear regression models.ResultsOlder youth participants displayed significantly higher HRV compared to younger participants (p

This article examines the representation of gift exchange in Ernest Gaines’s novel, A Lesson Before Dying. Drawing upon sociological and anthropological theories of the gift, it argues that gift exchange among the black community in the fictional town of Bayonne provides a mechanism of resistance to racial oppression in the Jim Crow South. The analysis first traces the history convergence of market and gift economies under slavery and the impact of these economic structures on African American dehumanization through the Jim Crow era. It then explores how A Lesson Before Dying reclaims gift exchange as a subversive practice that allows Jefferson, a man sentenced to death for a murder he did not commit, to reclaim his sense of manhood and reintegrate him into Bayonne’s black community. Ultimately, the novel prompts consideration of how gifts undermine systemic oppression in a racialized market economy.

Social behaviours are typically modelled using neighbour-modulated fitness, which focuses on individuals having their fitness altered by neighbours. However, these models are either interpreted using inclusive fitness, which focuses on individuals altering the fitness of neighbours, or not interpreted at all. This disconnect leads to interpretational mistakes and obscures the adaptive significance of behaviour. We bridge this gap by presenting a systematic methodology for constructing inclusive-fitness models. We find a behaviours inclusive-fitness effect by summing primary and secondary deviations in reproductive value. Primary deviations are the immediate result of a social interaction; for example, the cost and benefit of an altruistic act. Secondary deviations are compensatory effects that arise because the total reproductive value of the population is fixed; for example, the increased competition that follows an altruistic act. Compared to neighbour-modulated fitness methodologies, our approach is often simpler and reveals the models inclusive-fitness narrative clearly. We implement our methodology first in a homogeneous population, with supplementary examples of help under synergy, help in a viscous population and Creels paradox. We then implement our methodology in a class-structured population, where the advantages of our approach are most evident, with supplementary examples of altruism between age classes, and sex-ratio evolution.

FUNDAMENTO: Grande parte da relação entre o estado de saúde e o conhecimento sobre saúde e doença pode ser atribuída aos efeitos combinados de comportamento dísparrelacionado à saúde, condições ambientais e estruturas socioeconômicas, bem como o contato com a atenção à saúde e prestação da mesma. OBJETIVO: O objetivo do presente estudo foi descrever e comparar o conhecimento dos pacientes com doença arterial coronariana (DAC),incluídos em programas de reabilitação cardíaca (RC) no Brasil e no Canadá, sobre os fatores relacionados à DAC. MÉTODOS: Duas amostras de 300 pacientes brasileiros e 300 pacientes canadensesincluídos em RC foram comparadas transversalmente. Os pacientes brasileiros foram recrutados de dois centros de RC no Sul do Brasil, enquanto os pacientes canadenses foram recrutados de um centro de RC em Ontário. O conhecimento foi avaliado utilizando o Questionário de Educação de Doença Arterial Coronariana (CADE-Q), psicometricamente validado em Português e Inglês. Os dados foram processados por meio de estatísticas descritivas, post-hoc eteste t de Student. RESULTADOS: A pontuação média total de conhecimento para toda a amostra foi de 41,42 ± 9,3. Os entrevistados canadenses apresentaram pontuações totais de conhecimento significativamente maiores do que os entrevistados brasileiros. O domínio mais bem esclarecido em ambas as amostras foi o exercício físico.Em 13 de 19 questões, os entrevistados canadenses relataram pontuações de conhecimento significativamente maiores do que os entrevistados brasileiros. CONCLUSÃO: Pacientes ambulatoriais canadenses relataram conhecimento significativamente maior que suas contrapartes brasileiras. Os resultados também sugeremque um currículo educacional estruturado em programas de RC pode contribuir para um maior conhecimentodo paciente, o que pode em última análise facilitar as mudanças comportamentais.

Croziers paradox suggests that genetic kin recognition will not be evolutionarily stable. The problem is that more common tags (markers) are more likely to be recognized and helped. This causes common tags to increase in frequency, eliminating the genetic variability that is required for genetic kin recognition. Two potential solutions to this problem have been suggested: host-parasite coevolution and multiple social encounters. We show that the host-parasite coevolution hypothesis does not work as commonly assumed. Host-parasite coevolution only stabilizes kin recognition at a parasite resistance locus if parasites adapt rapidly to hosts and cause intermediate or high levels of damage (virulence). Additionally, when kin recognition is stabilized at a parasite resistance locus, this can have an additional cost of making hosts more susceptible to parasites. However, we show that if the genetic architecture is allowed to evolve, meaning natural selection can choose the recognition locus, genetic kin recognition is more likely to be stable. The reason for this is that host-parasite coevolution can maintain tag diversity at another (neutral) locus by genetic hitchhiking, allowing that other locus to be used for genetic kin recognition. These results suggest a way that host-parasite coevolution can resolve Croziers paradox, without making hosts more susceptible to parasites. However, the opportunity for multiple social encounters may provide a more robust resolution of Croziers paradox.

It has been hypothesized that horizontal gene transfer on plasmids can facilitate the evolution of cooperation, by allowing genes to jump between bacteria, and hence increase genetic relatedness at the cooperative loci. However, we show theoretically that horizontal gene transfer only appreciably increases relatedness when plasmids are rare, where there are many plasmid-free cells available to infect (many opportunities for horizontal gene transfer). In contrast, when plasmids are common, there are few opportunities for horizontal gene transfer, meaning relatedness is not appreciably increased, and so cooperation is not favored. Plasmids, therefore, evolve to be rare and cooperative, or common and noncooperative, meaning plasmid frequency and cooperativeness are never simultaneously high. The overall level of plasmid-mediated cooperation, given by the product of plasmid frequency and cooperativeness, is therefore consistently negligible or low.

While it is widely recognized that thinking is somehow costly, involving cognitive effort and producing mental fatigue, these costs have alternatively been assumed to exist, treated as the brain's assessment of lost opportunities, or suggested to be metabolic but with implausible biological bases. We present a model of cognitive cost based on the novel idea that the brain senses and plans for longer-term allocation of metabolic resources by purposively conserving brain activity. We identify several distinct ways the brain might control its metabolic output, and show how a control-theoretic model that models decision-making with an energy budget can explain cognitive effort avoidance in terms of an optimal allocation of limited energetic resources. The model accounts for both for subject responsiveness to reward and the detrimental effects of hypoglycemia on cognitive function. A critical component of the model is using astrocytic glycogen as a plausible basis for limited energetic reserves. Glycogen acts as an energy buffer that can temporarily support high neural activity beyond the rate supported by blood glucose supply. The published dynamics of glycogen depletion and repletion are consonant with a broad array of phenomena associated with cognitive cost. Our model thus subsumes both the cost/benefit and limited resource models of cognitive cost while retaining valuable contributions of each. We discuss how the rational control of metabolic resources could underpin the control of attention, working memory, cognitive lookahead, model-free vs. model-based policy learning as well as the pattern of generalization of cognitive improvements due to video-game training experiments.

Transmission heterogeneity, whereby a disproportionate fraction of pathogen transmission events result from a small number of individuals or geographic locations, is an inherent property of many, if not most, infectious disease systems. For vector-borne diseases, transmission heterogeneity is inferred from the distribution of the number of vectors per host, which could lead to significant bias in situations where vector abundance and transmission risk at the household do not correlate, as is the case with dengue virus (DENV). We used data from a contact tracing study to quantify the distribution of DENV acute infections within human activity spaces (AS), the collection of residential locations an individual routinely visits, and quantified measures of virus transmission heterogeneity from two consecutive dengue outbreaks (DENV-4 and DENV-2) that occurred in the city of Iquitos, Peru. Negative-binomial distributions and Pareto fractions showed evidence of strong overdispersion in the number of DENV infections by AS and identified super-spreading units (SSUs): i.e. AS where most infections occurred. Approximately 8% of AS were identified as SSUs, contributing to more than 50% of DENV infections. SSU occurrence was associated more with DENV-2 infection than with DENV-4, a predominance of inapparent infections (74% of all infections), households with high Aedes aegypti mosquito abundance, and high host susceptibility to the circulating DENV serotype. Marked heterogeneity in dengue case distribution, and the role of inapparent infections in defining it, highlight major challenges faced by reactive interventions if those transmission units contributing the most to transmission are not identified, prioritized, and effectively treated.

Entomological research studies on mosquito vector biology, vector competence, insecticide resistance, dispersal, and survival (using mark-release-recapture techniques) often rely on laboratory-reared mosquito colonies to produce large numbers of consistently reared, aged, and sized mosquitoes. We developed a low-cost blood feeding apparatus that supports temperatures consistent with warm blooded animals, using commonly available materials found in low resource environments. We compare our system ("Caserotek") to Hemotek and glass/membrane feeding methods. Two experiments were conducted with Aedes aegypti (Linnaeus 1762) and one with Anopheles darlingi (Root 1926) (Diptera: Culicidae); 3 replicates were conducted for each experiment. Aedes aegypti female mosquitoes were provided chicken blood once per week for 30 min (Experiment #1) for 14 days or 1 hour (Experiment #2) for 21 days. Anopheles darlingi were fed once for 1 hour (Experiment #3). Blood-feeding rates, survival rates, and egg production were calculated across replicates. Caserotek had a significantly higher 30-min engorgement rate (91.1%) than Hemotek (47.7%), and the glass feeder (29.3%) whereas for 1-hour feeding, Hemotek had a significantly lower engorgement rate than either of the other two devices (78% versus 91%). Thirty-day survival was similar among the feeding devices, ranging from 86% to 99%. Mean egg production was highest for the Caserotek feeder (32 eggs per female) compared to the glass feeder and Hemotek device (21-22 eggs per female). Our new artificial feeding system had significantly higher blood feeding rates than for more expensive artificial systems and was equivalent to other fitness parameters. Caserotek only requires the ability to boil water to maintain blood temperatures using a Styrofoam liner. It can be easily scaled up to large production facilities and used under austere conditions.

Dengue virus (DENV) transmission from humans to mosquitoes is a poorly documented, but critical component of DENV epidemiology. Magnitude of viremia is the primary determinant of successful human-to-mosquito DENV transmission. People with the same level of viremia, however, can vary in their infectiousness to mosquitoes as a function of other factors that remain to be elucidated. Here, we report on a field-based study in the city of Iquitos, Peru, where we conducted direct mosquito feedings on people naturally infected with DENV and that experienced mild illness. We also enrolled people naturally infected with Zika virus (ZIKV) after the introduction of ZIKV in Iquitos during the study period. Of the 54 study participants involved in direct mosquito feedings, 43 were infected with DENV-2, two with DENV-3, and nine with ZIKV. Our analysis excluded participants whose viremia was detectable at enrollment but undetectable at the time of mosquito feeding, which was the case for all participants with DENV-3 and ZIKV infections. We analyzed the probability of onward transmission during 50 feeding events involving 27 participants infected with DENV-2 based on the presence of infectious virus in mosquito saliva 7-16 days post blood meal. Transmission probability was positively associated with the level of viremia and duration of extrinsic incubation in the mosquito. In addition, transmission probability was influenced by the day of illness in a non-monotonic fashion; i.e., transmission probability increased until 2 days after symptom onset and decreased thereafter. We conclude that mildly ill DENV-infected humans with similar levels of viremia during the first two days after symptom onset will be most infectious to mosquitoes on the second day of their illness. Quantifying variation within and between people in their contribution to DENV transmission is essential to better understand the biological determinants of human infectiousness, parametrize epidemiological models, and improve disease surveillance and prevention strategies.

The mosquito Aedes aegypti is the vector of a number of medically-important viruses, including dengue virus, yellow fever virus, chikungunya virus, and Zika virus, and as such vector control is a key approach to managing the diseases they cause. Understanding the impact of vector control on these diseases is aided by first understanding its impact on Ae. aegypti population dynamics. A number of detail-rich models have been developed to couple the dynamics of the immature and adult stages of Ae. aegypti. The numerous assumptions of these models enable them to realistically characterize impacts of mosquito control, but they also constrain the ability of such models to reproduce empirical patterns that do not conform to the models' behavior. In contrast, statistical models afford sufficient flexibility to extract nuanced signals from noisy data, yet they have limited ability to make predictions about impacts of mosquito control on disease caused by pathogens that the mosquitoes transmit without extensive data on mosquitoes and disease. Here, we demonstrate how the differing strengths of mechanistic realism and statistical flexibility can be fused into a single model. Our analysis utilizes data from 176,352 household-level Ae. aegypti aspirator collections conducted during 1999-2011 in Iquitos, Peru. The key step in our approach is to calibrate a single parameter of the model to spatio-temporal abundance patterns predicted by a generalized additive model (GAM). In effect, this calibrated parameter absorbs residual variation in the abundance time-series not captured by other features of the mechanistic model. We then used this calibrated parameter and the literature-derived parameters in the agent-based model to explore Ae. aegypti population dynamics and the impact of insecticide spraying to kill adult mosquitoes. The baseline abundance predicted by the agent-based model closely matched that predicted by the GAM. Following spraying, the agent-based model predicted that mosquito abundance rebounds within about two months, commensurate with recent experimental data from Iquitos. Our approach was able to accurately reproduce abundance patterns in Iquitos and produce a realistic response to adulticide spraying, while retaining sufficient flexibility to be applied across a range of settings.

[This corrects the article DOI: 10.1371/journal.pntd.0009603.].

BackgroundSpatial repellents (SRs) have been widely used for prevention of mosquito bites, but their efficacy in reducing Aedes-borne viruses (ABV) has not been tested rigorously at large scale in Asia. To address this knowledge gap, a trial to evaluate the efficacy of Mosquito Shield™, a transfluthrin SR, was developed in Gampaha District of Sri Lanka across three Medical Officer of Health areas; i.e., Negombo, Wattala, and Kelaniya.MethodsThis trial is a cluster-randomized, placebo-controlled, double-blinded clinical trial. A total of ~14,430 subjects aged ≥ 6 months in 30 clusters (15 intervention, 15 placebo) from ~3900 households (HH) will be randomly selected for enrolment into a "febrile surveillance cohort." A subset of the surveillance cohort, ~3570 subjects aged ≥4-16 years that test seronegative (naïve) or are serologically positive for a previous single dengue virus (DENV) infection (monotypic) at baseline sampling, will be enrolled into a "longitudinal cohort" for measuring DENV infection based on laboratory-confirmed seroconversion during the trial. Persons identified positive for antibodies against multiple DENV serotypes (multitypic) at baseline will be monitored for secondary analyses. Active ABV disease will be assessed using an enhanced passive surveillance system with case ascertainment performed in designated healthcare facilities. Serum samples will be taken from longitudinal cohort subjects within 1-2 weeks of when intervention is first deployed (T0) with additional samples taken ~12 (T1) and ~24 months (T2) from baseline sampling. DENV seroconversion and ABV active disease rates from baseline (pre-intervention) and follow-up (post-intervention) samples will be compared between intervention and placebo clusters. Participating houses will be monitored entomologically (indoor adult Aedes aegypti population densities and adult female blood fed status) within 3 months before intervention deployment and monthly during the intervention phase. Entomological surveys will monitor indoor adult Ae. aegypti population densities and blood fed status. Dengue incidence in each cohort will be estimated and compared to determine the public health benefit of using an SR. Entomological parameters will be measured to determine if there are entomological correlates of SR efficacy that may be useful for the evaluation of new SR products.DiscussionThe trial will serve as an efficacy assessment of SR products in South Asia. Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of SRs in ABV control programs.Trial registrationSri Lanka Clinical Trial Registry SLCTR /2022/018. Registered on July 1, 2022.Clinicaltrialsgov NCT05452447 . Registered on July 11, 2022. The Universal Trial Number is U1111-1275-3055.

Current knowledge of dengue virus (DENV) transmission provides only a partial understanding of a complex and dynamic system yielding a public health track record that has more failures than successes. An important part of the problem is that the foundation for contemporary interventions includes a series of longstanding, but untested, assumptions based on a relatively small portion of the human population; i.e., people who are convenient to study because they manifest clinically apparent disease. Approaching dengue from the perspective of people with overt illness has produced an extensive body of useful literature. It has not, however, fully embraced heterogeneities in virus transmission dynamics that are increasingly recognized as key information still missing in the struggle to control the most important insect-transmitted viral infection of humans. Only in the last 20 years have there been significant efforts to carry out comprehensive longitudinal dengue studies. This manuscript provides the rationale and comprehensive, integrated description of the methodology for a five-year longitudinal cohort study based in the tropical city of Iquitos, in the heart of the Peruvian Amazon. Primary data collection for this study was completed in 2019. Although some manuscripts have been published to date, our principal objective here is to support subsequent publications by describing in detail the structure, methodology, and significance of a specific research program. Our project was designed to study people across the entire continuum of disease, with the ultimate goal of quantifying heterogeneities in human variables that affect DENV transmission dynamics and prevention. Because our study design is applicable to other Aedes transmitted viruses, we used it to gain insights into Zika virus (ZIKV) transmission when during the project period ZIKV was introduced and circulated in Iquitos. Our prospective contact cluster investigation design was initiated by detecttion of a person with a symptomatic DENV infection and then followed that person's immediate contacts. This allowed us to monitor individuals at high risk of DENV infection, including people with clinically inapparent and mild infections that are otherwise difficult to detect. We aimed to fill knowledge gaps by defining the contribution to DENV transmission dynamics of (1) the understudied majority of DENV-infected people with inapparent and mild infections and (2) epidemiological, entomological, and socio-behavioral sources of heterogeneity. By accounting for factors underlying variation in each person's contribution to transmission we sought to better determine the type and extent of effort needed to better prevent virus transmission and disease.

Spatial repellent (SR) products are envisioned to complement existing vector control methods through the continual release of volatile active ingredients (AI) providing: (i) protection against day-time and early-evening biting; (ii) protection in enclosed/semi-enclosed and peri-domestic spaces; (iii) various formulations to fit context-specific applications; and (iv) increased coverage over traditional control methods. SR product AIs also have demonstrated effect against insecticide-resistant vectors linked to malaria and Aedes-borne virus (ABV) transmission. Over the past two decades, key stakeholders, including World Health Organization (WHO) representatives, have met to discuss the role of SRs in reducing arthropod-borne diseases based on existing evidence. A key focus has been to establish a critical development path for SRs, including scientific, regulatory and social parameters that would constitute an outline for a SR target product profile, i.e. optimum product characteristics. The principal gap is the lack of epidemiological data demonstrating SR public health impact across a range of different ecological and epidemiological settings, to inform a WHO policy recommendation. Here we describe in brief trials that are designed to fulfill evidence needs for WHO assessment and initial projections of SR cost-effectiveness against malaria and dengue.

Hormonal therapy resistance remains a considerable barrier in the treatment of breast cancer. Activation of the Akt-PI3K-mTOR pathway plays an important role in hormonal therapy resistance. Our recent preclinical and clinical studies showed that the addition of a histone deacetylase inhibitor re-sensitized hormonal therapy resistant breast cancer to tamoxifen. As histone deacetylases are key regulators of Akt, we evaluated the effect of combined treatment with the histone deacetylase inhibitor PCI-24781 and tamoxifen on Akt in breast cancer cells. We demonstrate that while both histone deacetylase and estrogen receptor inhibition down regulate AKT mRNA and protein, their concerted effort results in down regulation of AKT activity with induction of cell death. Histone deacetylase inhibition exerts its effect on AKT mRNA through an estrogen receptor-dependent mechanism, primarily down regulating the most abundant isoform AKT1. Although siRNA depletion of AKT modestly induces cell death, when combined with an anti-estrogen, cytotoxicity is significantly enhanced. Thus, histone deacetylase regulation of AKT mRNA is a key mediator of this therapeutic combination and may represent a novel biomarker for predicting response to this regimen.

We aimed to compare the level of agreement between leg-to-leg bioelectrical impedance analysis (LBIA) and dual-energy X-ray absorptiometry (DXA) for assessing changes in body composition following exercise intervention among individuals with Type 2 diabetes mellitus (T2DM). Forty-four adults with T2DM, age 53.2±9.1 years; BMI 30.8±5.9 kg/m2 participated in a 6-month exercise program with pre and post intervention assessments of body composition. Fat free mass (FFM), % body fat (%FM) and fat mass (FM) were measured by LBIA (TBF-300A) and DXA. LBIA assessments of changes in %FM and FM post intervention showed good relative agreements with DXA variables (P

Presented herein are the outcomes of an experimental test involving a pioneering portable-active interrogation system designed for the nondestructive detection of special nuclear materials (SNMs). The system relies on the threshold energy neutron analysis concept and incorporates a portable deuterium–deuterium (DD) neutron generator producing a particle intensity of 5 × 107 n/s, coupled with three arrays of tensioned metastable fluid detectors (TMFDs) to detect secondary neutrons from the fissile material. In the presence of the fissile material, prompt fission neutrons are emitted, with an average energy of approximately 2 MeV, and around 30% of these neutrons have energies above that of the DD neutron source (2.45 MeV). The detection of a statistically significant neutron population exceeding this threshold firmly indicates the presence of SNM. TMFDs exhibit high sensitivity in efficiently detecting neutrons above the threshold while adeptly discriminating against neutrons below the threshold as well as gamma rays. This unique feature allows the interrogation system to maintain a lightweight profile without necessitating substantial shielding materials. The validation experiments involved the placement of 70 or 140 g masses of U-235 within a 1 m3 inspection volume. Measurements were carried out over 30 min intervals, repeated numerous times, both with and without U-235, at a DD neutron source intensity of 8 × 105 n/sec. Experimental count rates with natural uranium (NU) are consistently above those without NU. The probability of detection (PD) and probability of false alarm (PFA) were assessed utilizing these count rates. The DD neutron source intensity and inspection time were normalized at 5 × 107 n/sec and 90 s, respectively. The results indicated a PD of approximately 74% and 98% for detecting 70 and 140 g of U-235, respectively, with a PFA of <5%. These promising outcomes align with the specified PD (>90%) and PFA (<5%) targets outlined in ANSI standards. [ABSTRACT FROM AUTHOR]

Crozier's paradox suggests that genetic kin recognition will not be evolutionarily stable. The problem is that more common tags (markers) are more likely to be recognised and helped. This causes common tags to increase in frequency, and hence eliminates the genetic variability that is required for genetic kin recognition. It has therefore been assumed that genetic kin recognition can only be stable if there is some other factor maintaining tag diversity, such as the advantage of rare alleles in host-parasite interactions. We show that allowing for multiple social encounters before each social interaction can eliminate Crozier's paradox, because it allows individuals with rare tags to find others with the same tag. We also show that rare tags are better indicators of relatedness, and hence better at helping individuals avoid interactions with non-cooperative cheats. Consequently, genetic kin recognition provides an advantage to rare tags that maintains tag diversity, and stabilises itself.

Over half the world's population is at risk for viruses transmitted by Aedes mosquitoes, such as dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and geographic range of Aedes-borne viruses (ABVs) continue to expand. Rigorously proven vector control interventions that measure protective efficacy against ABV diseases are limited to Wolbachia in a single trial in Indonesia and do not include any chemical intervention. Spatial repellents, a new option for efficient deployment, are designed to decrease human exposure to ABVs by releasing active ingredients into the air that disrupt mosquito-human contact. A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru, to quantify the impact of a transfluthrin-based spatial repellent on human ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed rate, and parity status through mixed-effect difference-in-difference analyses. The spatial repellent significantly reduced ABV infection by 34.1% (one-sided 95% CI lower limit, 6.9%; one-sided P value = 0.0236, z = 1.98). Aedes aegypti abundance and blood-fed rates were significantly reduced by 28.6 (95% CI 24.1%, ∞); z = -9.11) and 12.4% (95% CI 4.2%, ∞); z = -2.43), respectively. Our trial provides conclusive statistical evidence from an appropriately powered, preplanned cluster-randomized controlled clinical trial of the impact of a chemical intervention, in this case a spatial repellent, to reduce the risk of ABV transmission compared to a placebo.

[This corrects the article DOI: 10.1371/journal.pntd.0006845.].

Vector-borne diseases are among the most burdensome infectious diseases worldwide with high burden to health systems in developing regions in the tropics. For many of these diseases, vector control to reduce human biting rates or arthropod populations remains the primary strategy for prevention. New vector control interventions intended to be marketed through public health channels must be assessed by the World Health Organization for public health value using data generated from large-scale trials integrating epidemiological endpoints of human health impact. Such phase III trials typically follow large numbers of study subjects to meet necessary power requirements for detecting significant differences between treatment arms, thereby generating substantive and complex datasets. Data is often gathered directly in the field, in resource-poor settings, leading to challenges in efficient data reporting and/or quality assurance. With advancing technology, mobile data collection (MDC) systems have been implemented in many studies to overcome these challenges. Here we describe the development and implementation of a MDC system during a randomized-cluster, placebo-controlled clinical trial evaluating the protective efficacy of a spatial repellent intervention in reducing human infection with Aedes-borne viruses (ABV) in the urban setting of Iquitos, Peru, as well as the data management system that supported it. We discuss the benefits, remaining capacity gaps and the key lessons learned from using a MDC system in this context in detail.

The importance of mosquitoes in human pathogen transmission has motivated major research efforts into mosquito biology in pursuit of more effective vector control measures. Aedes aegypti is a particular concern in tropical urban areas, where it is the primary vector of numerous flaviviruses, including the yellow fever, Zika, and dengue viruses. With an anthropophilic habit, Ae. aegypti prefers houses, human blood meals, and ovipositioning in water-filled containers. We hypothesized that this relatively simple ecological niche should allow us to predict the impacts of insecticidal control measures on mosquito populations. To do this, we use Skeeter Buster 2 (SB2), a stochastic, spatially explicit, mechanistic model of Ae. aegypti population biology. SB2 builds on Skeeter Buster, which reproduced equilibrium dynamics of Ae. aegypti in Iquitos, Peru. Our goal was to validate SB2 by predicting the response of mosquito populations to perturbations by indoor insecticidal spraying and widespread destructive insect surveys. To evaluate SB2, we conducted two field experiments in Iquitos, Peru: a smaller pilot study in 2013 (S-2013) followed by a larger experiment in 2014 (L-2014). Here, we compare model predictions with (previously reported) empirical results from these experiments. In both simulated and empirical populations, repeated spraying yielded substantial yet temporary reductions in adult densities. The proportional effects of spraying were broadly comparable between simulated and empirical results, but we found noteworthy differences. In particular, SB2 consistently over-estimated the proportion of nulliparous females and the proportion of containers holding immature mosquitoes. We also observed less temporal variation in simulated surveys of adult abundance relative to corresponding empirical observations. Our results indicate the presence of ecological heterogeneities or sampling processes not effectively represented by SB2. Although additional empirical research could further improve the accuracy and precision of SB2, our results underscore the importance of non-linear dynamics in the response of Ae. aegypti populations to perturbations, and suggest general limits to the fine-grained predictability of its population dynamics over space and time.