A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors.A secondary analysis was performed on a prospective registry data with low‐ to intermediate‐risk human papillomavirus–related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory–Head and Neck (MDASI‐HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal.Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE  leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate‐to‐high likelihoods of PM/ENE (>75% for short‐term and >40% for long‐term outcomes).In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols. The primary aim of transoral robotic surgery (TORS) in overall toxicity level reduction in eligible oropharyngeal squamous cell cancer (OPSCC) patients may be jeopardized in the presence of postoperative extranodal extension (ENE) and/or positive margin (PM) that necessitate adjuvant therapy. Our decision analysis model shows that Moderate‐to‐high likelihoods associated with postoperative PM or ENE that trigger adjuvant therapy leave definitive non‐surgical therapies as the optimal treatment for TORS‐eligible OPSCC patients leading to less overall toxicity burden. The premise of this study is to define the proportional likelihood of surgical risk features (and resultant indication for adjuvant therapy‐associated toxicity) and determine mathematically optimal decision between primary therapies: (chemo)RT or TORS. Put simply, we address the question of how numerically confident the surgeon and radiation oncologist must be in the risk of pretreatment pathologic margin positivity or ENE be to rationally select TORS for the purposes of minimizing toxicity assuming equivalent locoregional control.At present, the relative selection criteria for surgery are primarily qualitative and based on subjective assessment by the physician. Studies suggest that, at least in current practices, physicians are quite poor at predicting the necessity of adjuvant therapy based on presurgical or imaging risk features. This leaves the provider and patient with an upfront pretherapy choice: choose definitive (C)RT with The primary focus of the present study was to develop a decision support tool that aids in selecting the best primary treatment protocol by incorporating the likelihood of postoperative PM and/or ENE to quantify both overall therapy‐related burden level and swallowing function impairment based on short‐ and long‐term toxicities, using an existing prospective data set. The aims of this study were as follows: (i) to quantify the swallowing‐related toxicity levels of definitive therapies and TORS based on subjective and objective instruments using short‐term and long‐term assessments of toxicities and (ii) to determine the required confidence level of likelihood of ENE/PM to determine the optimal primary therapy and its' associated risk level. To achieve these aims, we incorporate the quantified expected swallowing‐related toxicity burden of each primary treatment based on probabilistic postoperative PM and/or ENE events. This is the first application of decision analysis, a widely established tool for decision‐making in uncertain environments. We use this tool to quantify the risk of postoperative swallowing‐related toxicities and the impact on quality of life, measured using highly reliable functional endpoints frequently used in OPSCC.22.1This secondary analysis was conducted using prospective registry data from the MD Anderson Oropharynx Cancer Registry (PA14‐0947) Patient‐Reported Outcomes and Function (PROF) Core. The PROF registry enrolls all consenting OPSCC/HNC patients at the University of Texas MD Anderson Cancer Center (MDACC). The sample for this secondary analysis included patients enrolled on PA14‐0914 from March 2015 to February 2018 with the following eligibility criteria: (i) cancer of the oropharynx and (ii) TORS, RT, or CRT as primary treatment approaches at MDACC. All primary treatment was determined by Multidisciplinary Tumor Board. Data analysis occurred under approval of the Institutional Review Board (protocol PA11‐0809).2.2Demographics and treatment characteristics of the cohort are listed in Table 2.3Prospective collection of clinician‐ and patient‐graded outcome measures occurred at routine timepoints. The MD Anderson Dysphagia Inventory (MDADI) is a patient‐administered 20‐item questionnaire that evaluates the impact of dysphagia on quality of life. The MDADI includes one question regarding global function and 19 items that focus on the physical, emotional and functional aspects of swallowing, which are pooled and averaged to obtain a composite score  to 100 ).2.4six measures were developed for this study. Each instrument was assessed for all treatment cohorts , TORS with adjuvant CRT (TORS+CRT)) pretherapy (baseline), 3–6 months and 18–24 months after primary treatment  were defined as the reduction in MDADI baseline score and the increment in MDASI baseline score, respectively, within 3–6 months. MDADI‐based and MDASI‐based absolute long‐term deterioration in swallowing function (ΔLMDADI and ΔLMDASI) were defined analogously with respect to 18–24 months scores. For each treatment cohort, DIGEST‐based short‐ and long‐term deteriorations in swallowing functions (DDIGEST and RDIGEST) were calculated as the fraction of baseline population whose DIGEST baseline grades evolved into any worse grade within 3–6 and 18–24 months after receiving therapy, respectively  as well as reducing the variability among of the constructed measures. For MDADI and MDASI scores, bootstrapping was employed based on the empirical distribution computed from the frequency of observed scores. The values of ΔSMDADI, ΔLMDADI, ΔSMDASI, and ΔLMDASI were calculated using bootstrapped data sets for each treatment cohort. For DIGEST grades, bootstrapping was employed based on the assumption that the evolution of baseline grades into 3–6 months and 18–24 months grades follows multinomial distribution based on the reported incidence RT's pN+ and pM+, respectively, ranging from 0 to 1) based on the assumption that when an adjuvant therapy is required, it is equally likely that the patient will undergo adjuvant RT or adjuvant CRT.  TORS versus definitive RT and (ii) TORS versus definitive CRT, based on the assumption that the patients studied under each scenario are eligible for both surgical and definitive therapy with comparable locoregional control and survival. For each scenario, the decision model was analyzed for each measure: using the collected measure values Table , the expcut‐off value for TORS  was computed as the highest expected toxicity burden of TORS under which TORS remains the optimal treatment.In each scenario, the optimal choice between TORS and the definitive therapy was made based on the observation that for both short‐ and long‐term swallowing‐related toxicity levels, the treatment protocol having lower expected toxicity burden is more favorable. For each scenario and for each short‐or long‐term measure, the risk associated with TORS (r) were developed as the fraction of possible combinations of postoperative ENE and PM likelihoods for which definitive therapy offers lower toxicity burden compared with TORS.The results of decision tree analysis were demonstrated as 2D heatmaps, for each measure, revealing the combination of likelihoods of postoperative ENE and PM for which TORS swallowing toxicity burden is lower than the definitive therapy. The heatmaps were also employed to derive individual postoperative ENE and PM likelihoods for which definitive therapy becomes the optimal treatment having lower swallowing toxicity level. Finally, to account for the inherent difficulty in pretherapy estimation of postoperative ENE/PM likelihoods, measure‐based 33.1Figure 3.1.1ΔSMDADI and ΔSMDASI, respectively) were always more severe compared with definitive RT  is given in Table 4not TORS alone, but rather some unquantified probability of double‐ or triple‐modality therapy . This is primarily due to absence of extreme presurgical certitude regarding of post‐TORS histopathological features, which makes it a challenging decision‐making problem to choose between initial TORS or definitive nonsurgical treatment protocols.Since the approval of TORS by FDA as a minimally invasive surgical treatment protocol for HNC patients, there have been several studies reporting on the success of TORS as an option for treatment of early‐stage oropharyngeal carcinomas due to its favorable oncologic outcomes and its potential to mitigate the toxicities incurred by patients in other surgical techniques or primary CRT.pretherapy physician‐estimated probability of margin positivity and ENE. Through quantifying posttherapy swallowing‐related toxicities using well‐established patient‐reported and objective instruments, the model in this study captures the probabilistic outcomes of TORS which in comparison with the definitive (C)RT's outcome can aid the clinical team in choosing the optimal treatment protocol. While objective instruments are developed based on standard test results, hence providing more concrete results in comparing the change in the patient's quality of life, they might be less indicative of the patient's lived experience. The developed decision support tool in this study is developed under the premise that the physician will include both objective and patient‐reported measures when deciding about the optimal therapy. The results of this model can also be utilized to compute the risk level associated with TORS in developing higher swallowing‐related toxicity burden compared with definitive (C)RT in the absence of pretherapy estimation of the likelihood of postoperative events that can trigger the need for adjuvant therapy.Decision analysis provides an integrated framework to study decision‐making scenarios that involve uncertain outcomes. The decision analysis model developed in this study incorporates the imputed pretherapy physic‐assessed statistical likelihood of the two major postoperative indicator events that trigger adjuvant therapy: Three observations are notable from the current analysis: (i) there are distinctly different optimal choices based on the probability of postoperative events that differ whether radiotherapy‐alone or chemoradiotherapy is the comparator for surgical treatment; (ii) there are divergent optimal choice of therapy regarding subjective multisymptom (MDASI), subjective swallowing (MDADI) or objective swallowing (DIGEST) is the toxicity metric of interest; and (iii) the choice of therapy based on early (3–6 month) swallowing outcomes may not reflect the optimal therapy selection for later time‐points (18–24 months).The decision analysis model in this work has its own limitations. It currently relies on a single institutional database with a cohort of 257 patients. Bootstrapping was used to mitigate the effects of small‐size population allowing the model to make assumptions as “real‐life” as possible. Furthermore, expected‐value decision analysis has its own disadvantages, namely the sensitivity to the probability values as well as measures. Sensitivity analysis was performed to determine the variation of TORS risk level as a function of the likelihood of postoperative events as well as associated quantified short‐ and long‐term toxicity of all treatment protocols. We would like to emphasize that while our model has been constructed based on single‐institutional data, it can be easily instantiated using validated possibly multi‐institutional data or even from randomized trials.Ultimately, the aim of this effort is to quantize decision‐making for HNC/OPSCC patients eligible for alternative treatment protocols. The vast majority of cases selected for definitive or surgical therapy  are typically made using heuristic physician‐decision processes, which appear to be speciously high estimates of the potential for single‐modality surgery. However, advanced approaches such as improved standardized radiologic assessment,5Our models demonstrated optimal decision thresholds for selection of surgical possibly with adjuvant therapy or organ preservation with (chemo)radiotherapy based on clinically‐representative subjective and objective toxicity outcomes. The resultant thresholds for physician certainty for prediction of clinical risk features necessitating adjuvant therapy should be considered with these decision tools as a component of multidisciplinary patient‐centric therapy selection for early‐stage oropharyngeal cancer patients.Mehdi Hemmati, Clifton D. Fuller, and Andrew J. Schaefer contributed to the study concept and design. Mehdi Hemmati implemented the decision support tool and performed the analysis. Mehdi Hemmati and Carly Barbon contributed to the data analysis. Abdallah S.R. Mohamed and Lisanne V. van Dijk contributed to data collection and interpretation. Amy C. Moreno, Neil D. Gross, Ryan P. Goepfert, Stephen Y. Lai, and Katherine A. Hutcheson contributed to the analysis and interpretation of the results. Mehdi Hemmati drafted the manuscript. All authors contributed to the interpretation of data and provided feedback on the manuscript.Dr. Fuller received/receives funding and salary support from directly related to this project from: NIH National Institute of Dental and Craniofacial Research (NIDCR) Academic Industrial Partnership Grant (R01DE028290); NIDCR Establishing Outcome Measures for Clinical Studies of Oral and Craniofacial Diseases and Conditions award (R01DE025248); NIH/NSF NCI Smart Connected Health Program (R01CA257814). Dr. Fuller received/receives funding and salary support from directly unrelated to this project from: NCI Parent Research Project Grant (R01CA258827); NCI Ruth L. Kirschstein NRSA Institutional Research Training Grant (T32CA261856); NIH NIDCR Exploratory/Developmental Research Grant Program (R21DE031082); National Institutes of Health (NIH) National Cancer Institute (NCI) Early Stage Development of Technologies in Biomedical Computing, Informatics, and Big Data Science Program (R01CA214825); NSF/NIH Joint Initiative on Quantitative Approaches to Biomedical Big Data program (R01CA225190); NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) Research Education Programs for Residents and Clinical Fellows Grant (R25EB025787); NCI Early Phase Clinical Trials in Imaging and Image‐Guided Interventions Program (1R01CA218148); NIH/NCI Cancer Center Support Grant (CCSG) Pilot Research Program Award from the UT MD Anderson CCSG Radiation Oncology and Cancer Imaging Program (P30CA016672); Small Business Innovation Research Grant Program a sub‐award from Oncospace, Inc. (R43CA254559); The Human BioMolecular Atlas Program (HuBMAP) Integration, Visualization & Engagement (HIVE) Initiative (OT2OD026675) sub‐award; Patient‐Centered Outcomes Research Institute  sub‐award from Princess Margaret Hospital; National Science Foundation (NSF) Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369). Dr. Fuller receives grant and infrastructure support from MD Anderson Cancer Center via the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program; the Program in Image‐guided Cancer Therapy; and the NIH/NCI Cancer Center Support Grant (CCSG) Radiation Oncology and Cancer Imaging Program (P30CA016672). Dr. Fuller has received direct industry grant/in‐kind support, honoraria, and travel funding from Elekta AB. TCS was supported by The University of Texas Health Science Center at Houston Center for Clinical and Translational Sciences TL1 Program (TL1 TR003169).The ethics approval was obtained from the University of Texas MD Anderson Cancer Center Institutional Review Board with protocol number: PA11‐0809.Appendix AClick here for additional data file.Appendix BClick here for additional data file.Appendix CClick here for additional data file.


The invasion of a novel host species can create a mismatch in host choice and offspring survival (performance) when native parasitoids attempt to exploit the invasive host without being able to circumvent its resistance mechanisms. Invasive hosts can therefore act as evolutionary trap reducing parasitoids' fitness and this may eventually lead to their extinction. Yet, escape from the trap can occur when parasitoids evolve behavioral avoidance or a physiological strategy compatible with the trap host, resulting in either host‐range expansion or a complete host‐shift. We developed an individual based model to investigate which conditions promote parasitoids to evolve behavioral preference that matches their performance, including host‐trap avoidance, and which conditions lead to adaptations to the unsuitable hosts. The model was inspired by solitary endo‐parasitoids attacking larval host stages. One important aspect of these conditions was reduced host survival during incompatible interaction, where a failed parasitization attempt by a parasitoid resulted not only in death of her offspring but also in host killing. This non‐reproductive host mortality had a strong influence on the likelihood of establishment of novel host–parasitoid relationship, in some cases constraining adaptation to the trap host species. Moreover, our model revealed that host‐search efficiency and genetic variation in host‐preference play a key role in the likelihood that parasitoids will include the suboptimal host in their host range, or will evolve behavioral avoidance resulting in specialization and host‐range conservation, respectively. Hence, invasive species might change the evolutionary trajectory of native parasitoid species, which is important for predicting biocontrol ability of native parasitoids towards novel hosts. Invasive species can act as an evolutionary trap for parasitoids when they are unsuitable for reproduction but indistinguishable from suitable hosts. Such incompatible interactions reduce parasitoids’ fitness and can reduce the viability of the population. Using an individual based model, we show how genetic variation in host preference and performance influence the evolution of generalization and specialization in response to an evolutionary trap. HoweverH. halys could facilitate population growth of its suitable stink bug host Podisus maculiventris, which is an important biocontrol agent. As host availability and suitability have a direct impact on parasitoid reproductive success, they can also shape the evolution of the parasitoid behavior and parasitization strategies. Hence, attacking and killing unsuitable hosts can change host population abundance of both suitable and unsuitable hosts , H2(t), and P(t), respectively.We simulate the evolution of two evolving traits, host preference behavior and parasitization strategy , in a population of parasitoids that has access to an original host species (host species 1) and a novel invader (host species 2). Generations are discrete and non‐overlapping for both host species and the parasitoid; we denote their population densities at the start of generation 2.2i (i = 1 or 2) is distributed following a Poisson distribution with mean:ni is the number of patches for host species i in the environment, ri is the maximum per‐capita offspring production rate, Hit denotes the total number of adult host individuals before density regulation , and Ki reflects the carrying capacity of host species i with respect to within‐species competition . This is relevant as most parasitoids seem to live relatively short and die before exhaustion of all their eggs and/or are able to replenish their egg supply during their life , whereas, on the extremes of the scale, individuals with q=+1 or q=−1 exclusively accept patches occupied by host species 1 or 2, respectively, and thus avoid the other host . Time intervals between encounters with a given host individual are drawn from an exponential distribution with mean τe . As a consequence of the stochasticity in the order and timing of host encounters, parasitoids tend to interact with a variable subset of the host individuals in a patch, rarely with all of them. Note, we thus assumed that hosts are distributed within the patch and are not clustered together. This can apply to parasitoids attacking the larval stage, but not egg masses since parasitoids do not require additional search time between encountering individual eggs once they have found the egg mass.Once an individual accepts a host patch, it proceeds to exploit the available hosts living there Figure . ParasitτdHi), it will be parasitized, incrementing the parasitoid's reproductive investment by one unit. The parasitoid's reproductive investment reflects energy invested in parasitization and egg production. Hosts can be parasitized multiple times; we assume that parasitoids do not discriminate against hosts that were previously attacked by another individual. Hence, our model allows for superparasitism: a host can be attacked multiple times by different conspecific females. The incidence of self‐superparasitism will be low as we assumed parasitoids to leave a patch once it encounters a host individual for a second time. Many parasitoids are indeed reported to be able to discriminate between already parasitized hosts  of the parasitoid, and the timing of host and parasitoid offspring development , either the parasitoid offspring develops when it is compatible with the host, or the host survives the parasitoid attack when they are incompatible. Thus, in this scenario, either the host or the new parasitoid offspring survives the interaction. In the other model scenario with non‐reproductive host killing (scenario 2), parasitoid offspring can initially develop in the incompatible hosts to the point that the host is killed, but parasitoid offspring cannot successfully complete development in an incompatible host. Host death can come about due to, for example, damage inflicted by parasitoid attack and/or self‐harm through mounting an immune defense. Hence, when the host is parasitized, it always dies, whether or not it is compatible. Thus, in this scenario, either the host or the parasitoid survives parasitization.The outcome of an incompatible host–parasitoid interaction differs between scenario 1 and 2  and thus have a lower success rate of completion of development and offspring survival , and surviving hosts are collected to determine H1t+1 and H2t+1, the density of hosts at the start of the next time step.After the outcome of all interactions has been decided, the parasitoid offspring replace the parental generation ; incompatible with the invader (host 2) and q=0 . Host population densities were initialized at their equilibrium density in the absence of parasitization (Hi*=Ki∙lnri). Genetic variation in host preference and parasitization strategy was introduced by a low rate of mutation . Accordingly, specialists can mutate to the generalist tactic, which can mutate to either one of the specialist tactics with equal probability, but specialists cannot mutate to become specialized for the other host species in a single mutational step.Hymenoptera parasitoids are haplodiploid, but for simplicity and comparability with other host–parasitoid models , the parasitoid's host‐use strategy that determines its physiological compatibility with either of the host species or both, would influence  host‐range evolution. Next, we also considered genetic variation in host‐preference behavior (q), the parasitoid's inherent choice to lay eggs in certain hosts. We did this under different costs by examining the influence of (1) the relative developmental success of generalist parasitoids (determined by different parameter ratios τdP1/τdP3) and (2) parasitoid search time (depending on parameter τs). Search time may vary depending on environmental conditions: a low search time might reflect a resource rich‐environment in which patches are clustered, whereas a relatively high search time might reflect a resource‐poor environment in which host‐habitat patches are sparse and/or more difficult to locate. The latter conditions imply a higher evolutionary costs of exerting host preference, as the decision to reject a patch would necessitate a large time investment for finding a more suitable patch, compromising the amount of time remaining for reproduction.Multiple traits can be involved in host‐range and host adaptation, which might evolve independently in response to selection. We therefore first investigated how genetic variation in parasitization tactic  and lost time exploiting unsuitable host patches. As such, host 2 acted as an “evolutionary trap.” When specialists attempt to exploit an incompatible host, this either had no effect on host survival (model scenario 1), or resulted in host death without parasitoid offspring, that is, non‐reproductive host killing (scenario 2)  and the behavioral trait host preference to evolve (q). Host preference relies on individuals rejecting host patches, which is a costly decision if the time needed to find a patch is high. Parasitoids that exhibit an avoidance for either host species can therefore increase their total reproductive output by selecting suitable host‐patches that match their parasitization tactic (performance) and thus lose less time exploiting unsuitable hosts. The evolution of host species preference can however be constrained by the search efficiency of individuals in a given environment as this sets their time budget to find their preferred hosts , remaining a mismatch in host choice and performance Figure . Only whSpecialists of host 1 that exhibit non‐reproductive host killing of host 2, however, tend to dominate and constrain physiological host‐range expansion and specialization on the  suboptimal host when search efficiency is low and when generalists exhibit relative high efficiencies Figure . First c4L. heterotoma attacking the invasive D. suzukii fruit‐fly. Although this fruit‐fly species is unsuitable for parasitoid offspring development due to its high resistance  species calls for understanding and predicting not only the—short‐term—ecological impact on native species in the invaded range but also their impact over evolutionary time , we considered that attacking unsuitable hosts either leaves the host unharmed or, on the other extreme, is fatal for the host. The latter often occurs in host–parasitoid systems  meaning that unfertilized eggs arise through meiosis and develop into males, and females arise after mating through fusion of two gametes and are diploid  and resistance ; formal analysis (lead); methodology ; writing – original draft (lead); writing – review and editing . Leo W. Beukeboom: Conceptualization ; methodology ; writing – review and editing . Bregje Wertheim: Conceptualization ; methodology ; writing – review and editing . G. Sander van Doorn: Conceptualization ; methodology (lead); writing – review and editing .The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.https://doi.org/10.5061/dryad.31zcrjdp6. The model code can be found in the Appendix This article has earned an Open Data badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at: Appendix S1Click here for additional data file.


The aim was to explore nurses' preparedness to expand their practice to prescribe medicines under a supervision model.This was a cross‐sectional study.A convenience sample of Australian nurses recruited from memberships of State‐based Nursing and Midwifery Unions and professional bodies from diverse care settings. Nurses undertook an online researcher‐constructed survey between March and July 2021 to identify current prescribing practices, motivations for undertaking education in prescribing and perceived barriers to implementation of nurse prescribing under supervision. Data related to demographics, nursing experience and barriers to becoming a prescriber were analysed descriptively. Logistic regression was used to model nursing experience variables with desire to become a prescriber.n = 3645, 82%) reporting they were highly likely to expand their practice to prescribe medicines under supervision. The main motivations to prescribe were to enhance patient care and job satisfaction. Nurses were more likely to want to prescribe if they had <10 years experience , held a bachelor's degree  or higher qualification . Most reported lack of acknowledgement of increased responsibility and workloads , and insufficient organizational support  may prevent uptake of nurse prescribing.A total of 4424 nurses participated with the majority (Most Australian nurses demonstrated their preparedness to embrace the role of prescribing under supervision. The perceived barriers identified in this study can inform future implementation of this expanded nursing role.The Nursing and Midwifery Board of Australia has proposed a standard of practice to enable nurses to prescribe under supervision. Models of nurse prescribing are being considered globally to address population needs. Successful adoption of this practice is dependent on aspects such as key personnel's acceptance of the initiative. The workforce readiness and barriers highlighted in this study can inform implementation at policy and organizational levels. As the primary aim of the study was exploratory and descriptive, no ‘a priori’ sample size was calculated; however, a final sample with a minimum of 500 participants was sufficient to adequately power the logistic regression analyses  comprising senior academics with expertise in nursing, nurse‐led models of care, policy, pharmacy and non‐medical prescribing and informed by a recent integrative review conducted by the research team  and factors enabling implementation of nurse prescribing (12 items) were measured on a five‐point Likert response scale with responses 0 = ect HWA,  definitiThe final survey was uploaded into Key Survey. An invitation email containing the survey link was distributed to the members of four state‐based nursing and midwifery unions including the Queensland Nurses and Midwives' Union, the New South Wales Nurses and Midwives' Association, the Australian Nursing and Midwifery Federation ‐Victoria and the Australian Nursing and Midwifery Federation ‐South Australia, professional nursing bodies and networks of the research team. The survey was anonymous and no identifiable information was collected from participants, ensuring participant confidentiality.3.5Ethics approval was granted by the Queensland University of Technology Human Research Ethics Committee (#2000000418).3.6All statistical analyses were performed using IBM SPSS Statistics (version 27). Descriptive statistics were calculated (count and percentage) for demographic data, data relating to nursing experience and items that made it unlikely for nurses to want to become a prescriber. Current prescribing practices across states, qualification level and years of experience were explored by computing cross‐tabulations. Counts and percentages as well as means and standard deviations were calculated for Likert scale items relating to participant views and ranked motivations. Normality of the distribution was tested with the absolute values of the skewness and kurtosis because of the large sample size Kim, . All datNo desire’ = extremely unlikely, unlikely and neutral and ‘desire’ = extremely likely and likely. Univariate and multivariate logistic regression was used to model nursing experience variables  and state with the desire to become a prescriber. These variables were included as past research has indicated that experience has an impact on views towards nurse prescribing , over 40 years of age , possessed a bachelor's degree or higher  and received their nursing qualification in Australia . Half of the participants were employed full‐time , and participants worked predominantly in public hospitals , in inpatient settings  and in clinical roles . Participants were employed in a wide variety of practice contexts, with a large proportion working in medical, surgical, community, primary health and emergency areas. Table A total of 4424 registered nurses participated in the study, representing approximately 1.3% of all registered nurses in Australia AGDoH, . Most pa4.2n = 3163, 71.49%,) with just over one‐quarter of nurses involved in initiating medicines based on a protocol or formulary . Prescribing practices appeared to vary according to state, years of experience and level of qualification with larger proportions of nurses prescribing, initiating, adjusting or ceasing medication in Queensland and New South Wales, amongst those with a post‐graduate qualification or higher, and for participants with less than 10 years nursing experience.Current prescribing practices are reported in Table 4.3improve the use of nurses' knowledge, skills and capability (92% agree or strongly agree), increase access to nurse‐led models of care (90% agree or strongly agree) and improve patients' healthcare experience (86% agree or strongly agree). The highest rated factors that would enable implementation of nurse prescribing included supportive legislation and policy (92% agree or strongly agree), appropriate mentors (91% agree or strongly agree) and models of nursing care that optimize use of nurse prescribing (92% agree or strongly agree).Participants’ views about the implementation of nurse prescribing under supervision and the factors that may enable this practice are shown in Table n = 3309, 80.84%) felt that patients who receive a prescription from a nurse prescriber (where a fee is charged to the patient), should be eligible for the Medicare Benefits Schedule, and a similar number  felt that patient access to the Pharmaceutical Benefits Scheme should be facilitated by the inclusion of nurse prescribers for relevant medicines. Note: The provision of healthcare in Australia is subsidized by the government. The Medicare Benefits Schedule and Pharmaceutical Benefits Scheme detail the medical services and medicines eligible for subsidy, respectively.A majority of participants (p < 0.001) and had higher education qualifications . Participants with more than 10 years of nursing experience were statistically significantly less likely to report wanting to become a prescriber compared with those with less than 10 years experience , and if they worked in settings outside of public, private, community or aged care .A high proportion of respondents indicated that they would be likely to become a prescriber if specific education was available (82% somewhat or extremely likely), although proportions varied across age groups, states and qualification level. At the univariate level, wanting to become a prescriber was significantly associated with state, level of qualification, years of experience and workplace setting. Adjusted odds ratios Table  indicateimproved care to patients , followed by improved job satisfaction , improved professional reputation  and contribution to the multi‐disciplinary team . Increased remuneration was the lowest motivator in relative terms .For participants who indicated they would want to become a prescriber if education was available, the highest ranked motivation was for not believing there would be organizational support (43.15%), not changing the patient care they provide (21.02%) and not being prepared to take on extra responsibility (15.80%).The most common reasons for participants to be unlikely to become a prescriber are available in Supplementary Table 5not only relevant to the nursing profession, but to a range of stakeholders including policymakers; independent prescribers  and healthcare organizations planning to introduce expanded prescribing practices. The vast majority of the participants expressed the high likelihood of undertaking further study to expand their practice to prescribe medicine under a supervision model. Most nurses working in Australia do not currently prescribe medicines, however as many as one‐third are already engaged in initiating, adjusting or ceasing medicines using formulary and protocols.To our knowledge, this is the first study in Australia to explore the readiness of the nursing workforce to embrace prescribing under supervision. We believe the findings from this study are Compared to other states, nurses working in Victoria were most likely to have the desire to become prescribers. It is difficult to speculate the true reason. It is important that future research explores system‐level contextual factors. Participants aged less than 50 years, with less than 10 years experience and those with higher qualifications were more likely to want to become a prescriber than nurses over the age of 50 years, with more than 10 years experience or those with certificate level qualifications. This finding is consistent with research by Pool et al.  who founNurses perceived that prescribing under supervision would improve use of nurse knowledge, skills and capability, as well as support nurse‐led models of care improving patient experiences. Their key motivation to prescribe were improving patient care and gaining greater job satisfaction. Those who were unlikely to become a prescriber did not believe their organization would support it. Evidence suggests that lack of organizational support for service innovation will prevent initial adoption and sustainability .None.https://publons.com/publon/10.1111/jan.15367.The peer review history for this article is available at Table S1Click here for additional data file.


Over the past two decades, cardiac resynchronization therapy (CRT) became an established treatment option for patients with symptomatic heart failure. Current guideline criteria recommend implanting a CRT in patients with reduced left ventricular (LV) ejection fraction (LVEF ≤ 35%) and conduction delays (a QRS ≥ 130 ms on ECG)—preferably in those patients with a left bundle branch block (LBBB) morphology. Although the underlying problem is of an electrical nature—i.e., a myocardial conduction delay—the result in the left ventricle is of a mechanical nature: a dyssynchrony between the early activated septal wall and the late-activated lateral wall. Correcting this mechanical dyssynchrony by means of bi-ventricular pacing, in order to resynchronize the contraction pattern, is the main mode of action of CRT. Typically, CRT is considered successful when patients show an improvement in heart failure symptoms and/or reverse remodelling of their left ventricle . Such patients are commonly labelled as ‘responder’.What Are Reasons for Non-Response?One significant limitation of CRT is, however, the high rate of ‘non-response’. Recent data repeatedly indicate that about one out of three patients do not show an improvement after CRT —even wheTwo main problems can be identified: (I) the absence of a ‘treatable substrate’ for CRT, and (II) reasons that reduce the likelihood of response . While improving the selection criteria for CRT has been a topic of controversy for several years—and continues to be so—reasons that reduce or even prevent response are still very much underexplored.For a CRT device—which is aimed at resynchronizing the heart—the treatable substrate is the presence of dyssynchrony. Since about one out three patients currently implanted with a CRT do not show signs of mechanical dyssynchrony , it appeWhereas it is well established that the presence of myocardial scarring in the lateral wall of the left ventricle can severely hamper the efficacy of CRT—since scarred myocardium in the lateral wall would not transmit the electrical signal of the LV lead—the effect of scarring in other LV walls is understudied. Recent studies suggest that the presence of scarring in the septal wall also significantly impacts the ability to respond to CRT, since a scarred septum cannot recover contractile function during the remodelling process after CRT implantation ,4. WhileSome data suggest that a subgroup of patients exists with such severe LV dysfunction that they might have surpassed the optimal therapeutic window where CRT is most beneficial . Indeed,Pacing-related issues are not to be underestimated as reason for poor response after CRT implantation. Whereas some problems can already be identified shortly after implantation—e.g., suboptimal atrio-ventricular timing, arrhythmias or suboptimal LV lead positioning—others require a longer follow-up, such as is the case of patients with loss of bi-ventricular pacing . In suchWhat Can We Do about the High Rate of Non-Response?Lastly, other intrinsic and external reasons for reduced response after CRT are still underexplored. Examples include the effect of (I) reduced right ventricular systolic function and/or increased pulmonary pressures; (II) diastolic dysfunction; (III) left atrial dyssynchrony; and (IV) anaemia.Evidence is building that the selection criteria for CRT should be updated. Particularly assessing the presence of mechanical dyssynchrony in heart failure patients with conduction delays appears promising to select those patients in whom CRT will likely be successful. Evidence from large ongoing randomized trials—to be expected in the forthcoming years —could further strengthen results from recent observational trials.Another focus should be improving awareness that the presence of scarring in the left ventricle is an important determinant of non-response to CRT. The current gold standard for myocardial scar detection—cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE)—is widely available, but currently still underused. Other potential alternatives to CMR—which is hampered by a relatively high cost and difficulty of use in patients with already implanted devices or severe renal dysfunction (both of which are common in CRT candidates)—should further be explored.In addition to a potentially promising role for imaging in improving the selection of CRT candidates, new ECG-based markers also suggest that a more careful analysis of patients’ ECG could provide useful insights. A number of techniques—among which vectorcardiography—appear promising in selecting those patients likely to respond to CRT. Evidence from a large ongoing observational trial will provide more insight into their strength .Perhaps even more important than new selection markers is further improving our understanding on the pathophysiology behind heart failure with conduction delays and mechanical dyssynchrony. With better insight, a better selection of patients—and thus a better responder/non-responder balance—can be expected. Particularly, a better serial follow-up of patients with conduction delays—even when they do not show signs of LV dysfunction—to monitor any potential remodelling as well as presence of mechanical dyssynchrony could provide more insight into the progressive deterioration caused by this disease.Together with continued technological developments, hope exists to optimize the use of resynchronization therapy and to deliver this technique to all patients that could benefit from it.Journal of Clinical Medicine—dedicated to “Finding New Insights in Cardiac Resynchronization Therapy and the Pathophysiology Behind Left Ventricular Dyssynchrony”—aims to pave the way towards the objectives provided above. We welcomed original research and review articles that: (1) shed new light on pathophysiology; (2) highlight and provide answers to unmet clinical needs; (3) provide insights that could expand or improve guideline indications; and (4) discuss future directions in research. Manuscripts with both a clinical and a translational focus  were considered.In conclusion, this Special Issue in the


The a priori hypotheses assumed the intervention would increase preventive services, and treatment demand was met.To evaluate the impact of an intervention consisting of a 1‐day continuing professional development (CPD) education programme on the International Caries Classification and Management System  of 12‐month pre‐ (baseline) and post‐intervention analysis was performed.p‐value <0.05). The DiD analysis confirmed the above findings in the intervention group, while other preventive services declined. In the intervention group, the performance benchmark for oral prophylaxis or scale and clean and oral hygiene instructions was met at baseline and post‐intervention.The intervention group demonstrated increases in topical fluoride application and dietary analysis and advice services. The standard care group had increases in oral prophylaxis or scale and clean, topical fluoride application and oral hygiene instructions (Only a few preventive services had already met the performance benchmark. The intervention was associated with varied changes to preventive and non‐preventive dental services. More robust study design addressing the study limitations and validating the performance benchmark is required. The project objectives were to.Report on the type and rates of preventive, restorative and extraction procedures provided 12 months before the intervention and 12‐month post‐intervention for children 0–12 years of ageApply the Difference‐In‐Difference (DiD) analysis to control for bias and make inferences on the impact of the intervention.Report on the type and rates of the different dental procedures provided to children 0–12 years of age against the developed performance benchmarksThis pilot study aimed to evaluate an intervention promoting the MID approach in an Australian community dental agency. The intervention consisted of a 1‐day ICCMS™ training as a CPD activity and monthly performance feedback against a developed performance benchmark. Two 2A quasi non‐randomized controlled trial with convenience sampling method was adopted. Four dental services sites within the community dental agency were included in this study. In the intervention group, 14 dental practitioners were recruited from the two dental service sites with a skill mix profile of 4.8 full‐time equivalent (FTE) dentists and 3.2 FTE dental/oral health therapists. The other remaining 15 dental practitioners working at the other two dental service sites were denoted as the standard care group (control) with a skill mix of 5.9 FTE dentists and 4.2 FTE dental/oral health therapists. Both groups had a dentist to dental/oral health therapist ratio of approximately 1.5:1. Participating dental practitioners at times are required to work ‘cross‐sites’ within the community dental agency.Rationale and principles for ICCMS™Theory of ICCMS™Clinical protocol of ICCMS™Case study examples of ICCMS™Enablers and barriers to ICCMS™Dental practitioners in the intervention group received a 1‐day CPD programme on the ICCMS™ in July 2017 delivered by the two researchers (TMN and HC), whereas dental practitioners in the standard care group did not. The topics covered in the 1‐day CPD programme included the following:Preventive Dental Services , andNon‐Preventive Dental Services  or using preformed metal stainless steel crowns (SSC) and dental extractions).The types of dental services provided by the community dental agency were classified into:TM and MID approach.Since there is no formal performance benchmark for preventive dental services, the research team in consultation with the organization's leadership dental team developed one based on the prevalence of dental caries and gingivitis for Australian children aged 0–12, consistent with the ICCMSMonthly performance feedback based on dental services provided in the last 12 months by the intervention group was summarized based on the classified category of the type of service and compared against the performance benchmark. Feedback on how well the intervention group performed, using a traffic light reporting system, was presented to the participating dental practitioners by the senior team leader at regular monthly team meetings. Figure The traffic light reporting system was adapted from a clinical education intervention reported in the literature and has been shown to improve the behaviour of undergraduate dental students.z‐tests determined whether there was a statistically significant difference (p < 0.05) for dental treatment services received by children provided by dental practitioners in the intervention and standard care groups.De‐identified dental services item codes provided in dental clinics and school‐based dental services for children aged 0–12 years were obtained for dental services provided for baseline (pre‐intervention) and 12‐month post‐intervention analysis for the 2016/17 and 2017/18 financial years. Two‐sample proportions The magnitude of the intervention effect was calculated using the DiD approach. The DiD study design can make inferences where randomized controlled trials are impractical, infeasible or unethical.The DiD approach is commonly used for studies, which involve data collected for other purposes such as information from electronic health records or medical claims datasets. Essentially, it is a before‐after comparison test of an intervention group against a comparator group with similar characteristics and exposure to potential confounders.Pre, and IPost for before and after, respectively. Likewise, the comparator group is denoted, CPre and CPost for before and after, respectively. The DiD estimate is derived as (IPre ‐ IPost)‐ (CPre ‐ CPost), which determines the magnitude of the effect and the direction of the effect, that is a positive value indicates an increase, a negative value indicates a decrease, and a zero value indicate no difference.To calculate the DiD, the effect on the intervention group is denoted IMicrosoft Excel 365 (Microsoft Corporation) and Stata 12 IC (StataCorp) was used to manage and analyse the data. This study received approval as a quality assurance project QA/18/PH/4 from Peninsula Health and completed according to the principles of the Declaration of Helsinki.3z‐tests comparing children who received dental services by dental practitioners in the intervention and standard care groups.At baseline, the total number of children aged 0–12 years was 3265 in the intervention group and 4973 in the standard care group. At 12‐month post‐intervention, there were 2853 in the intervention group and 4698 in the standard care group. Table p < 0.05).The intervention group received more dental services in almost all service types than the standard care group. The intervention group demonstrated a significant increase in topical fluoride application and dietary analysis and advice services, while other preventive dental services were significantly reduced. Most preventive dental services in the standard care group increased, but only oral prophylaxis or scale and clean, topical fluoride applications and oral hygiene instructions services were statistically significant  was noted in both groups. The provision of SSC significantly increased by a fold of 1.5 and 2.6 in the intervention and standard care group, respectively. The magnitudes of the changes are shown in Table The performance benchmark changed from being unmet at baseline and met at 12‐month post‐intervention for dietary analysis and advice in the standard care group, while other services maintained their performance status Table . Prevent4a priori hypothesis for this study was to test if the intervention would lead to an increase in the provision of preventive dental services aligned with the ICCMSTM. However, our findings demonstrated that the intervention group was associated with a significant increase in only a few types of preventive dental services, specifically, topical fluoride application and dietary analysis and advice services. The provision of the other five preventive dental services had significantly decreased.The first ™ approach, but differentiating the type of technique cannot be quantified since the dental item code was not available for HCT during the study period.We expected a decrease in the number of posterior conventional restorations and dental extractions as a result of providing more early detection and preventive dental services. Significant reduction in these services was found in both groups Table , which ip < 0.05).Before the commencement of this study, all dental practitioners at Peninsula Health had a CPD programme on HCT. It appears the HCT was well adopted, particularly by dental practitioners in the intervention groups as reflected in the higher SSC services at baseline compared to the standard care group . The uptake for providing more SSC services continued to increase at 12 months as evidenced by significant differences for both groups compared to baseline (™ and MID approach, which is person‐centred centred and emphasises regular preventive maintenance.This study found that there were only a few types of preventive dental services provided in the intervention and standard care group that met the developed performance benchmark. A specific focus is required to increase the substantial deficit for the number of services provided for routine oral examination and topical fluoride application services. Our findings support future research is required to facilitate the adoption and adherence to the ICCMSThe DiD calculation showed the intervention was only associated with a substantial increase of topical fluoride application and dietary analysis and advice services. Although an unfavourable direction for the oral prophylaxis or scaling and clean and oral hygiene instructions was noted from the DiD analysis, these preventive services had already met the performance benchmark at baseline of 22.0 and 42.0 per 100 individuals, respectively.The improvement in the delivery of only some preventive dental services could potentially be associated with the current behaviour of dental practitioners and the Victorian public funding system. Two government reports reported the lack of prevention and early intervention services in the management of oral disease provided by Australian public dental programmes.Other possible contributing factors, such as the attitudes and beliefs of the dental practitioners on oral disease management, and the perceptions of the clients regarding preventive and treatment services, were not controlled nor collected in this study. A qualitative research study has since been conducted to identify those contributing factors and explore the reasons for the increase in only a few types of preventive dental services found in this quantitative analysis. A separate publication on the qualitative study is forthcoming.There are several limitations of this study that may have impacted the results. A fundamental limitation is that the researchers did not control for the potential confounder that dental practitioners in both groups may have received previous education and training on the ICCMS™ and MID approach or had undertaken them during the study period.The positive differences for all preventive dental services except for dietary analysis and advice services at baseline and 12‐month post‐intervention indicates dental practitioners in the intervention group may be more aligned to the ICCMS™ and MID approach. The true results of the intervention may also have affected if there was contamination due to dental practitioners working cross‐sites. Furthermore, since there were data limitations where aggregate information was provided and not of individual observations, testing for sensitivity and falsification using the DiD analysis approach was not possible.TM and MID approach, and validating the developed performance benchmark would be needed to support the work of this pilot study.Although the sample size was adequate at the dental service site level, the study was confined to one community dental agency in the Melbourne metropolitan area, which limits the generalizability of the results. Furthermore, robust study design and more extensive research to explore the enablers and barriers to the ICCMSA strength of this study is it shows that the 1‐day CPD training together with regular performance feedback could tentatively be beneficial to increase more preventive dental services, particularly in topical fluoride application and dietary analysis and advice services. Given dental practitioners in the intervention group provides dental services for all ages, it would be interesting to observe if there has been any impact from the intervention with clients aged older than 12 years.TM and MID approach by other dental practitioners. Previous work has shown system‐level strategies, including multimethod/multiphased CPD,™ and MID approach.Online education and training could be established to minimize the cost of the intervention, thereby making access to the CPD training flexible and increase the uptake of the ICCMS5TM education training as well as assessing the appropriateness of the developed performance benchmarks.The 1‐day CPD education programme on ICCMS™ together with monthly performance feedback could promote the MID approach, particularly concerning topical fluoride application and dietary analysis and advice services for children aged 0–12 in an Australian community dental agency. However, the DiD analysis and comparison against the developed performance benchmarks showed the delivery of routine oral examination, bitewing intra‐oral radiographs, and topical fluoride applications required improvement. Additional research at a larger scale is needed, within the community dental agency and with other dental service providers, to explore the benefits of the ICCMS66.1There is limited quantitative evidence from the Australian public dental sector, demonstrating whether dental services provided are consistent with the MID approach.6.2This research demonstrated a 1‐day CPD education programme, and monthly performance feedback provided to dental practitioners was associated with positive changes in a few preventive dental services evaluated at 12‐month post‐intervention.6.3TM and the MID approach.More research is needed to investigate how to support dental practitioners to promote the ICCMSMr Nguyen, Dr Tonmukayakul and Professor Calache have nothing to disclose.T.M.N, U.T. and H.C. conceived the ideas; T.M.N. analysed the data and led the writing; T.M.N., U.T. and H.C. interpreted the results, contributed and finalized the critical intellectual content.


Poephila acuticauda) has two hybridizing subspecies that differ in bill color (red and yellow), and the yellow bill phenotype appears to have introgressed ~350 km eastward following secondary contact. To examine the role of mate choice on bill color introgression, we performed behavioral assays using natural and manipulated bill colors. We found an assortative female mating preference for males of their own subspecies when bill color was not manipulated. However, we did not find this assortative preference in trials based on artificially manipulated bill color. This could suggest that assortative preference is not fixed entirely on bill color and instead may be based on a different trait  or a combination of traits, or alternatively may be due to lower statistical power alongside the bill manipulations being unconvincing to the female choosers. Intriguingly, we find a bias in the inheritance of bill color in captive bred F1 hybrid females. Previous modeling suggests that assortative mate preference and this kind of partial dominance in the underlying genes may together contribute to introgression, making the genetic architecture of bill color in this system a priority for future research.Mating behavior can play a key role in speciation by inhibiting or facilitating gene flow between closely related taxa. Hybrid zones facilitate a direct examination of mating behavior and the traits involved in establishing species barriers. The long‐tailed finch ( We investigate whether mate choice might play a role in the unidirectional introgression of yellow bill color between subspecies of the long‐tailed finch. Females demonstrate an assortative mate preference for unmanipulated males of their own subspecies. However, the evidence that females base this assortative preference on bill color is equivocal. Both natural and experimentally manipulated bill colors were used. Given that the genetic architecture of traits  can play an important role in trait inheritance and the dynamics of introgression following hybridization, we also examined bill color of captive‐bred first generation (F22.1P. a. acuticauda or P. a. hecki) held in aviaries at Macquarie University in Sydney, Australia. Wild‐caught P. a. acuticauda  individuals were sourced from two populations in Western Australia: Mount House  and Nelson's Hole . Wild‐caught P. a. hecki  individuals were sourced from October Creek, Northern Territory , red (Rimmel London 310 Red), black (Rimmel London 800 Black out), or transparent . These red and yellow nail polish colors were selected as they appeared to be the closest match to the bill colors of each subspecies by the human eye. To assess how effective our bill manipulations were we used reflectance spectrophotometry to measure bill color of both unmanipulated individuals and individuals with manipulated bills, following published protocols  and the effect size of this difference is small  and the effect size of this difference is notable . This suggests that our use of H3 is capturing the bulk of the main spectral variation and should therefore appropriately represent the yellow and red phenotypes. The ‘black’ manipulation was intended to mimic the coloration of juveniles, and the manipulation successfully resulted in a uniform and low reflectance across the avian color spectrum. There was no significant difference between the hues of bills prior to and following treatment with our clear control manipulation .We compared the hue of manipulated bills to the range of variation observed in natural bills of each subspecies. The hue of the artificial ‘yellow’ manipulation was not significantly different from the natural yellow color of 2.3The first set of trials performed exposed a focal (choosing) bird to four stimulus birds, all with manipulated bill colors. We describe the methodology and results of these ‘four‐way trials’ for completeness and transparency, however, they have issues (outlined below) that limit the interpretation of these trials. A second set of trials  with refined methodology were subsequently performed and we will focus on those.The four‐way mate choice trials were performed in a four‐armed wooden preference apparatus with the focal (choosing) bird starting on a perch in the middle Figure . Each arThe limitations of these four‐way trials included (1) low sample sizes, due to the logistical difficulty of manipulating bill color (and removing those bill manipulations), exacerbated by the fact that trials had to be further subdivided by whether the ‘clear’ bill manipulation bird had a naturally red or yellow bill color; (2) the complicated design and low sample sizes meant that potentially confounding factors cannot be statistically accounted for , and (3) the number of stimuli in the design meant that focal birds may have experienced sensory overload and were unable to express a clear preference. This is consistent with other laboratory groups studying avian behavior that transitioned away from four‐way trials around the time these were performed  were performed using only female focal birds, who were provided just two stimulus males at a time, with separate trials for manipulated and unmanipulated stimulus bill colors and an increased overall sample size. For these two‐way trials the existing four‐way testing apparatus was modified by blocking off two opposite arms Figure . We wantacuticauda female and 46 with a hecki female, each female given a single trial. Of these, 70 were successful . Of the successful trials, 32 were with acuticauda females  and 38 were with hecki females . For the trials with artificial bill colors for the stimulus birds, fewer were performed due to the challenges associated with bill color manipulation. A total of 40 trials were performed using 16 hecki females and 24 acuticauda females. Of these, 36 were successful . Of the successful trials, 13 had acuticauda females  and 23 had hecki females .We performed a total of 87 trials with stimulus birds having natural bill colors, 41 with an 2.51) hybrids via reflectance spectrophotometry using the methods outlined above. F1 hybrids were produced by establishing mixed breeding pairs containing a male from a parental subspecies with a female from the other parental subspecies in small aviaries at Macquarie University. As one candidate locus for bill color is located on the Z chromosome . In trials with yellow focal females and natural stimulus bill colors there are two extreme values, but excluding these points produces the same results, so we report results with the full dataset. As there were fewer manipulated trials, we calculated the power they had to detect any effect identified in the natural trials. We analyzed the four‐way trials using linear models in a similar fashion to the two‐way trials  and sex and cross (and their interaction) as dependent variables.For the two‐way trials, we assessed the data in four groups: whether the focal female was 3hecki spent a significantly greater proportion of time with hecki than acuticauda males  may be driven by the much smaller sample size than natural trials  resulting in low statistical power to identify a similar sized effect . In the four‐way trials, we observed no clear evidence for mate preference by males or by acuticauda females, and although hecki females showed a preference for yellow bills, this was only in trials with a clear yellow bill : F1 females with an acuticauda father and a hecki mother had significantly yellower bills than any of the other groups  of F4Poephila acuticauda). We found no evidence for a common female preference for yellow billed individuals across both subspecies that could drive the observed introgression of yellow bill color in the wild. Our results instead suggest that females have a weak assortative preference for their own subspecies, whereby acuticauda females prefer naturally yellow‐billed males and hecki females prefer naturally red‐billed males. However, this assortative preference weakens or disappears when females are exposed to two males of their own subspecies with bills manipulated to be red or yellow, suggesting that the assortative preference is multimodal or based on another trait that differs between the subspecies . A potential source of the assortative mate preference observed in this study is sexual imprinting, whereby offspring develop their mate preferences by learning during a short sensitive period, based on the phenotypes of the parents that reared them  as found in Hooper et al. ; Data curation (Lead); Formal analysis (Lead); Funding acquisition (Supporting); Investigation (Supporting); Visualization (Supporting); Writing – Original Draft (Lead); Writing – Review and Editing . Fiona Finch: Investigation ; methodology ; writing – review and editing (supporting). Marianne Peso: Investigation ; methodology ; writing – review and editing (supporting). Erica van Rooij: Investigation ; methodology ; writing – review and editing (supporting). Daniel Marc Hooper: Conceptualization ; formal analysis (supporting); visualization (lead); writing – original draft ; writing – review and editing . Melissah Rowe: Conceptualization ; formal analysis (supporting); writing – original draft ; writing – review and editing . Simon Griffith: Conceptualization ; funding acquisition (lead); investigation ; methodology ; project administration ; writing – original draft ; writing – review and editing .The authors declare no conflicts of interest.Supporting information S1.Click here for additional data file.Supporting information S2.Click here for additional data file.


The proportion of humans suffering from age‐related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie—and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched‐chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality—the specific composition of dietary protein—may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging. Creative solutions are needed to combat increasing rates of metabolic disease and promote healthy aging. This review summarizes the latest research on protein and branched‐chain amino acid restriction as interventions to alter metabolism to extend lifespan and reduce frailty in model organisms and humans. The authors discuss the potential mechanisms underpinning these dietary interventions and postulate future directions of the field, which may include personalized nutrition therapy. It is now generally believed that the restriction of protein in a CR diet is not great enough to fully explain the benefits of CR . mTORC1 regulates a wide variety of downstream biological processes—most notably those related to growth and proliferation such as ribosomal, protein, nucleotide, and lipid synthesis through integration of nutrient and hormonal cues; this has been reviewed in great detail elsewhere . Unlike mTORC1, GCN2 senses amino acid deprivation by binding to uncharged transfer RNA molecules (tRNA) and stalled ribosomes   —a valine‐specific catabolic intermediate—the intermediates of BCAA catabolism are conjugated to CoA and thus confined to the mitochondria  acetylation by BCAA‐derived acetyl‐CoA, resulting in decreased binding of PRDM16 to peroxisome proliferator‐activated receptor γ (PPARγ). This leads to the suppression of browning genes and therefore contributes to diet‐induced obesity. Interestingly, this same study identified that telmisartan, an FDA‐approved antihypertensive medication, inhibits BCATm, increasing iWAT browning and energy expenditure, and reducing adiposity in mice.Resistance to diet‐induced obesity was also replicated in a recent study of adipose‐ and iWAT‐specific Ppm1k in liver of Zucker fatty rats, which are obese, hyperphagic, and hyperinsulinemic, lowers hepatic triglycerides and improves glycemia, likely through action on ATP citrate lyase (ACL), rather than BCKDH, as described above , and BCAA accumulation along with high glucose levels produces insulin‐resistant cardiac tissue  with BCAA and insulin levels. One meta‐analysis found several single nucleotide polymorphisms (SNPs) in genomic regions of BCAA catabolism and connected these SNPs to elevated BCAAs and insulin resistance  of five common BCAA metabolic pathway SNPs in conjunction with dietary BCAA intake to parse out determinants of T2DM risk. This study was conducted in a Chinese population of almost 10,000 individuals and determined that a high GRS plus high intake of BCAAs conveyed the greatest risk for T2DM development. Interestingly, high BCAA intake positively correlated with HbA1c and circulating BCAA levels in participants with a high but not a low GRS  expression in adipose and muscle  and mouse models of the disease, and brain BCAA catabolism is impaired in the brains of models of AD by downregulation of 8.5There are many factors that need to be considered in the application of experimental diets to human patients, mainly safety and feasibility. BCAA‐restricted diets could conceptually be used as a weight loss and insulin‐sensitizing intervention or promote healthy longevity. Restricting BCAAs in diet‐induced obese mice induced rapid weight loss . MSUD is an autosomal recessive disease in which mutations in BCKDH genes require limitation of the BCAAs to prevent neurotoxic buildup of BCAAs and BCKAs. Over the course of a week, the intentional reduction in dietary BCAAs resulted in reduced circulating BCAAs by 50%. Additionally, the intervention slightly reduced insulin resistance as measured by Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR)  does not alter the metabolic response to isoleucine restriction (Yu et al., The role of FGF21 in response to specific restriction of isoleucine is a bit clearer; isoleucine restriction strongly raises FGF21 levels and induces Fgf21. These results suggest that many PR outcomes may be independent of changes in FGF21.Interestingly, our laboratory recently discovered that the metabolic and molecular response to PR has sex‐ and strain‐dependent effects (Green et al., 12There are still questions surrounding dietary AAs, metabolism, and longevity that remain unanswered by the current literature, especially in humans. The work discussed above raises new questions about how the amount and quality of protein intake influences health, and suggests that perhaps these dietary recommendations will need to be personalized. For example, as detailed earlier, the elderly may need to consume more BCAAs to prevent muscle loss and stave off frailty, while athletes may need to consume more BCAAs to build and maintain muscle. These protein or BCAA recommendations may be personalized based on one’s circulating amino acid levels and genes, allowing us to find the best diet for each person. Further research into the molecular mechanisms which underlie the benefits of BCAA and protein restriction may allow the development of pharmaceuticals to mimic these dietary interventions.13D.W.L has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.All of the authors contributed to all aspects of the article.


Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics. Geroscience‐guided approaches seek to delay the onset and progression of chronic conditions by targeting the pathways of aging. This approach is likely to improve overall health in old age by addressing aging—the largest risk factor for the leading causes of morbidity. Here, we propose the creation of a standardized process for evaluating FDA‐approved drugs for their geroscience potential, permitting the prioritization of efforts and investments for translating geroscience discoveries. ACEiangiotensin‐converting enzyme inhibitorACSAcute Coronary SyndromeADAlzheimer’s diseaseADAS‐cogAlzheimer's Disease Assessment Scale–Cognitive SubscaleARBangiotensin receptor blockerBCCbasal cell carcinomaBEZ235dactolisibBMDbone mineral densityBPblood pressureCADCoronary Artery DiseasecIMTcoronary (artery) intimal media thicknessCKDchronic kidney diseaseCRCcolorectal cancerCVcardiovascularCVAcerebrovascular accidentDMdiabetes mellitusESRDend‐stage renal diseaseGFRglomerular filtration rateHFheart failureHRhazard ratioHRCThigh‐resolution chest CTHTNhypertensionIFNinterferonILDinterstitial lung diseaseIPFidiopathic pulmonary fibrosisIRRincidence rate ratioMACEmajor adverse cardiovascular eventMCImild cognitive impairmentMImyocardial infarctionMMSEmini mental status evaluationORodds ratioRAD001everolimusRCTrandomized controlled trialRRrelative riskSASPsenescence‐associated secretory phenotypeSRRstandardized rate ratioSUsulfonylureaT2Ddiabetes mellitus, type 21Geroscience represents a novel paradigm whereby biological aging is recognized as the major modifiable driver of age‐related diseases and other late‐life conditions  is such a study that has been under development for the last few years, and whose basic principles have been developed in consultation with the FDA , a well‐characterized, multicentered study to evaluate gerotherapeutics, as well as non‐ITP rodent lifespan studies . This approach meant that drugs that have shown some clinical benefits but have not shown extension of lifespan in preclinical rodent models were excluded from further analysis. These findings were then updated with drugs tested in the ITP since 2019 (DrugAge Build 3 was released in July 2019). Nutraceutical/supplemental products were excluded, and only FDA‐approved drugs were included (n = 9 drugs). Search was then split into preclinical  and clinical  using the search terms and datasets as described in Figure We conducted mining of the DrugAge (Build 3) database for drugs that extend lifespan . Thereby, promising gerotherapeutics that have significant basic geroscience rationale, yet currently lack supportive data from human subject studies were not penalized.2.3Of the 6 points evaluating basic or preclinical factors, up to 2 points were assigned each for targeting hallmarks of aging, improving preclinical healthspan and preclinical lifespan each, with the breakdown as follows: (i) 1 point assigned for less than 3 hallmarks, 2 points assigned for 3 or more hallmarks; (ii) 2 points assigned for effect on healthspan parameters; (iii) 1 point assigned for lifespan tested outside ITP, 2 points assigned for a significant increase in lifespan within ITP  Healthspan: drug needed to demonstrate that it targeted at least one age‐related disease/pathologic process which it was not intended to treat, with 1 point assigned for observational studies and 3 points for interventional, randomized controlled trials (RCTs); (ii) mortality: drug needed to demonstrate that it reduced all‐cause mortality or death from a disease which it was not intended to treat, with 1 point assigned for observational studies and 3 points assigned for RCTs.3Using the process detailed in Figure 3.13.1.1Gerotherapeutics in preclinical models were primarily evaluated for their ability to extend rodent lifespan Table . Robust 3.1.2In addition to lifespan effects, we evaluated the evidence of potential gerotherapeutics on improving healthspan in preclinical models of aging and age‐related diseases, where the action of the drug was attributed to their non‐primary target or mechanism. Metformin displayed strong evidence in targeting conditions that were beyond its antihyperglycemic function  in corneal endothelial cells  Macromolecular damage and adaptation to stress; (2) epigenetic effects, stem cell renewal and regeneration; (3) proteostasis, inflammation (and senescence); and (4) metabolism  are conflicted, at least in part due to marked variability in study populations, agents, and dosages used, comparators (placebo or active comparators), open‐label addition of other agents and achieved blood pressure goals  the preclinical and clinical evidence supporting the claims for each of the nine potential gerotherapeutics selected. Surprisingly, with a score of 12/12, the best evidence was found for a relatively new class of drugs, the SGLT2i, which showed better promise than other known potential gerotherapeutics such as metformin, rapamycin, or acarbose.The profound effects of SGLT2i on healthspan and lifespan in both animal models and humans may result from the pleiotropic effects beyond renal glucose and sodium handling, including improved mitochondrial function, restoration of autophagy, and promotion of ketogenesis‐dependent dampening of mTORC1 hyperactivation  and to findings from humans . Although for translational purposes, knowledge from human studies is likely to have more weight than studies in rodents, we gave both equal values for several reasons: (1) The literature on potential gerotherapeutics in rodents is quite extensive and, while many of these studies are too recent to have been considered for clinical trials yet, their potential should not be dismissed based solely on their “novelty”; (2) some mouse studies, like the ITP, are quite robust, thus enhancing their predictive value as potential gerotherapeutics; (3) because of their highly controlled nature, studies in mice often have fewer caveats than similar studies in humans. Thus, while it could be argued that preclinical geroscience knowledge becomes less relevant if a drug has solid data on decreasing all‐cause mortality in humans, we decided it was not appropriate at this time to penalize potential drugs that have strong preclinical evidence.In evaluating the preclinical data for specific drugs, we only considered rodent models. This approach excludes a sizable amount of literature on lifespan extension in lower organisms such as yeast, nematodes, and flies, but since the interventions have not yet been tested in mammals, approval for a trial in humans would likely take decades. Furthermore, in evaluating data on mouse longevity  we gave more weight to studies that have been validated by the ITP, a well‐characterized, multicentered study that is widely accepted in the field to determine the translatability of gerotherapeutics, based on their rigor and their use of a genetically heterogeneous model that attempts to approximate the diversity in human populations. From the clinical side, we considered drugs that affect either all‐cause mortality (the most relevant parameter) or have a positive effect on unrelated diseases not intended to be the primary target of the drug. Thus, we were interested, for example, in a diabetes drug known to affect molecular pathways involved in aging, and that has been shown to also have a positive effect on incident off‐target age‐related diseases, such as cancer, dementia, or CVD.Our approach restricted potential gerotherapeutics that affect hallmarks of aging without known effects on healthspan, as well as those that have not been tested for lifespan in animals. Two potential gerotherapeutics that failed in this test are colchicine (an anti‐inflammatory agent) and bisphosphonates (used in the treatment of osteoporosis). Interestingly, several studies show that bisphosphonates can decrease mortality even within critical care settings, where their action is clearly not related to their usual therapeutic use in osteoporosis. So, while these and possibly other FDA‐approved drugs might indeed show great potential as gerotherapeutics, they have not met our inclusion criteria, and their analysis is beyond the scope of this paper. The available data suggests that both colchicine and bisphosphonates should be rapidly tested in the ITP or in other centers, to confirm improved healthspan and lifespan in mammals.In addition to the classes of drugs discussed above, another type of molecular entity that was not considered in our analysis deserves special mention; we did not consider nutraceuticals, several of which have indeed been shown to positively affect both healthspan and lifespan . They not only lack robust pharmacological and clinical data, but also fail to serve our main purpose of identifying FDA‐approved drugs with the goal of repurposing them as gerotherapeutics that can reduce the rate of deterioration accompanying aging.bona fide sex‐specific analysis. Another issue that is relevant for translating findings from geroscience‐guided animal studies into humans is the question of dosing. For instance, the doses of rapamycin or rapalogs used both in mice (ITP studies) and human  contributed to the literature search, writing, and editing of the manuscript.