Toward understanding the endocrine regulation of diverse facultative migration strategies.

Migration is an important event in the annual cycle of many animals that facilitates the use of resources that vary across space and time. It can occur with regular and predictable timing, as in obligate migration, or with much greater flexibility, as in facultative migration. Most research aimed at understanding the endocrine mechanisms regulating the transition to a migratory stage has focused on obligate migration, whereas less is known about facultative forms of migration. One challenge for research into the endocrine regulation of facultative migration is that facultative migrations encompass a diverse array of migratory movements. Here, we present a framework to describe and conceptualize variation in facultative migrations that focuses on conditions at departure. Within the context of this framework, we review potential endocrine mechanisms involved in the initiation of facultative migrations in vertebrates. We first focus on glucocorticoids, which have been the subject of most research on the topic. We then examine other potential hormones and neurohormones that have received less attention, but are exciting candidates to consider. We conclude by highlighting areas where future research is particularly needed.

Does capacity to produce androgens underlie variation in female ornamentation and territoriality in White-shouldered Fairywren (Malurus alboscapulatus)?

Historic bias toward study of sex hormones and sexual ornamentation in males currently constrains our perspective of hormone-behavior-phenotype relationships. Resolving how ornamented female phenotypes evolve is particularly important for understanding the diversity of social signals across taxa. Studies of both males and females in taxa with variable female phenotypes are needed to establish whether sexes share mechanisms underlying expression of signaling phenotypes and behavior. White-shouldered Fairywren (Malurus alboscapulatus) subspecies vary in female ornamentation, baseline circulating androgens, and response to territorial intrusion. The moretoni ornamented female subspecies is characterized by higher female, but lower male baseline androgens, and a stronger pair territorial response relative to pairs from the lorentzi unornamented female subspecies. Here we address whether subspecific differences in female ornamentation, baseline androgens, and pair territoriality are associated with ability to elevate androgens following gonadotropin releasing hormone (GnRH) challenge and in response to simulated territorial intrusion. We find that subspecies do not differ in their capacity to produce androgens in either sex following GnRH or simulated territorial intrusion (STI) challenges. STI-induced androgens were predictive of degree of response to territorial intrusions in females only, but the direction of the effect was mixed. GnRH-induced androgens did not correlate with response to simulated intruders, nor did females sampled during intrusion elevate androgens relative to flushed controls, suggesting that increased androgens are not necessary for the expression of territorial defense behaviors. Collectively, our results suggest that capacity to produce androgens does not underlie subspecific patterns of female ornamentation, territoriality, and baseline plasma androgens.

Telomere length predicts timing and intensity of migratory behaviour in a nomadic songbird.

Our understanding of state-dependent behaviour is reliant on identifying physiological indicators of condition. Telomeres are of growing interest for understanding behaviour as they capture differences in biological state and residual lifespan. To understand the significance of variable telomere lengths for behaviour and test two hypotheses describing the relationship between telomeres and behaviour (i.e. the causation and the selective adoption hypotheses), we assessed if telomere lengths are longitudinally repeatable traits related to spring migratory behaviour in captive pine siskins (Spinus pinus). Pine siskins are nomadic songbirds that exhibit highly flexible, facultative migrations, including a period of spring nomadism. Captive individuals exhibit extensive variation in spring migratory restlessness and are an excellent system for mechanistic studies of migratory behaviour. Telomere lengths were found to be significantly repeatable (R = 0.51) over four months, and shorter pre-migratory telomeres were associated with earlier and more intense expression of spring nocturnal migratory restlessness. Telomere dynamics did not vary with migratory behaviour. Our results describe the relationship between telomere length and migratory behaviour and provide support for the selective adoption hypothesis. More broadly, we provide a novel perspective on the significance of variable telomere lengths for animal behaviour and the timing of annual cycle events.

Environmental Cue Integration and Phenology in a Changing World.

Many organisms use environmental cues to time events in their annual cycle, such as reproduction and migration, with the appropriate timing of such events impacting survival and reproduction. As the climate changes, evolved mechanisms of cue use may facilitate or limit the capacity of organisms to adjust phenology accordingly, and organisms often integrate multiple cues to fine-tune the timing of annual events. Yet, our understanding of how suites of cues are integrated to generate observed patterns of seasonal timing remains nascent. We present an overarching framework to describe variation in the process of cue integration in the context of seasonal timing. This framework incorporates both cue dependency and cue interaction. We then summarize how existing empirical findings across a range of vertebrate species and life cycle events fit into this framework. Finally, we use a theoretical model to explore how variation in modes of cue integration may impact the ability of organisms to adjust phenology adaptively in the face of climate change. Such a theoretical approach can facilitate the exploration of complex scenarios that present challenges to study in vivo but capture important complexity of the natural world.

Social environment influences termination of nomadic migration.

The final stage of migration, when animals terminate migratory movements and transition to a more sedentary state, remains the least understood phase of migration. Whereas migrants that return to the same locations each year may use mechanisms associated with locating a specific destination, migrants with low site fidelity, such as nomadic migrants, may rely on local environmental cues to determine when to cease migratory movements. Using an experiment with captive birds, we tested whether the presence of a conspecific influences the termination of migration, indicated by changes in behaviour and physiology, in a nomadic migrant (the pine siskin, Spinus pinus). We paired migratory birds with a non-migratory individual or left migratory and non-migratory individuals unpaired. Migratory paired birds had a significant decline in nocturnal activity immediately after pairing and activity levels remained lower two weeks later, with significant declines in energetic reserves and flight muscle size also observed. By contrast, migratory unpaired birds maintained high levels of activity and energetic reserves. These results provide evidence for a role of the social environment in migratory termination decisions. Social cues may be particularly useful in nomadic migrants, such as pine siskins, to facilitate settling in high quality, but unfamiliar, habitats.

Corticosterone's roles in avian migration: Assessment of three hypotheses.

While corticosterone (CORT) is often suggested to be an important hormone regulating processes necessary for avian migration, there has been no systematic assessment of CORT's role in migration. Prior to migration, birds increase fat stores and flight muscle size to prepare for the high energetic costs associated with long-distance flight. After attaining sufficient energetic stores, birds then make the actual decision to depart from their origin site. Once en route birds alternate between periods of flight and stopovers, during which they rest and refuel for their next bouts of endurance flight. Here, we evaluate three non-mutually exclusive hypotheses that have been proposed in the literature for CORT's role in migration. (1) CORT facilitates physiological preparations for migration [e.g. hyperphagia, fattening, and flight muscle hypertrophy]. (2) CORT stimulates departure from origin or stopover sites. (3) CORT supports sustained migratory travel. After examining the literature to test predictions stemming from each of these three hypotheses, we found weak support for a role of CORT in physiological preparation for migration. However, we found moderate support for a role of CORT in stimulating departures, as CORT increases immediately prior to departure and is higher when migratory restlessness is displayed. We also found moderate support for the hypothesis that CORT helps maintain sustained travel, as CORT is generally higher during periods of flight, though few studies have tested this hypothesis. We provide recommendations for future studies that would help to further resolve the role of CORT in migration.

Migratory state and patterns of steroid hormone regulation in the pectoralis muscle of a nomadic migrant, the pine siskin (Spinus pinus).

The endocrine system is known to mediate responses to environmental change and transitions between different life stages (e.g., a non-breeding to a breeding life stage). Previous works from the field of environmental endocrinology have primarily focused on changes in circulating hormones, but a comprehensive understanding of endocrine signaling pathways requires studying changes in additional endocrine components (e.g., receptor densities) in a diversity of contexts and life stages. Migratory birds, for instance, can exhibit dramatic changes in their physiology and behavior, and both sex steroids as well as glucocorticoids are proposed mediators of the transition into a migratory state. However, the role of changes in endocrine signaling components within integral target tissues, such as flight muscles, in modulating the transition into a migratory state remains poorly understood. Here, we examined changes in gene expression levels of and correlational patterns (i.e., integration) between 8 endocrine signaling components associated with either glucocorticoids or sex steroid signaling in the pectoralis muscles of a nomadic migratory bird, the pine siskin (Spinus pinus). The pectoralis muscle is essential to migratory flight and undergoes conspicuous changes in preparation for migration, including hypertrophy. We focus on endocrine receptors and enzymes (e.g., 5α-reductase) that modulate the signaling capacity of circulating hormones within target tissues and may influence either catabolic or anabolic functioning within the pectoralis. Endocrine signaling components were compared between captive birds sampled prior to the expression of vernal migratory preparation and during the expression of a vernal migratory state. While birds exhibited differences in the size and color of the flight muscle and behavioral shifts indicative of a migratory state (i.e., zugunruhe), none of the measured endocrine components differed before and after the transition into the migratory state. Patterns of integration amongst all genes did, however, differ between the two life stages, suggesting the contrasting demands of different life stages may shape entire endocrine signaling networks within target tissues rather than individual components. Our work aligns with previous endocrine studies on pine siskins and, viewed together, suggest additional studies are needed to understand the endocrine system's role in mediating the development and progression of the vernal migratory state in this species. Further, the patterns observed in pine siskins, a nomadic migrant, differ from previous studies on obligate migrants and suggest that different mechanisms or interactions between endocrine signaling components may mediate the migratory transition in nomadic migrants.

HIV Incidence by Male Circumcision Status From the Population-Based HIV Impact Assessment Surveys-Eight Sub-Saharan African Countries, 2015-2017.

BACKGROUND: Male circumcision (MC) offers men lifelong partial protection from heterosexually acquired HIV infection. The impact of MC on HIV incidence has not been quantified in nationally representative samples. Data from the population-based HIV impact assessments were used to compare HIV incidence by MC status in countries implementing voluntary medical MC (VMMC) programs. METHODS: Data were pooled from population-based HIV impact assessments conducted in Eswatini, Lesotho, Malawi, Namibia, Tanzania, Uganda, Zambia, and Zimbabwe from 2015 to 2017. Incidence was measured using a recent infection testing algorithm and analyzed by self-reported MC status distinguishing between medical and nonmedical MC. Country, marital status, urban setting, sexual risk behaviors, and mean population HIV viral load among women as an indicator of treatment scale-up were included in a random-effects logistic regression model using pooled survey weights. Analyses were age stratified (15-34 and 35-59 years). Annualized incidence rates and 95% confidence intervals (CIs) and incidence differences were calculated between medically circumcised and uncircumcised men. RESULTS: Men 15-34 years reporting medical MC had lower HIV incidence than uncircumcised men [0.04% (95% CI: 0.00% to 0.10%) versus 0.34% (95% CI: 0.10% to 0.57%), respectively; P value = 0.01]; whereas among men 35-59 years, there was no significant incidence difference [1.36% (95% CI: 0.32% to 2.39%) versus 0.55% (95% CI: 0.14% to 0.67%), respectively; P value = 0.14]. DISCUSSION: Medical MC was associated with lower HIV incidence in men aged 15-34 years in nationally representative surveys in Africa. These findings are consistent with the expected ongoing VMMC program impact and highlight the importance of VMMC for the HIV response in Africa.

Seasonal regulation of behaviour: what role do hormone receptors play?

Many animals differentially express behaviours across the annual cycle as life stages are coordinated with seasonal environmental conditions. Understanding of the mechanistic basis of such seasonal changes in behaviour has traditionally focused on the role of changes in circulating hormone levels. However, it is increasingly apparent that other endocrine regulation mechanisms such as changes in local hormone synthesis and receptor abundance also play a role. Here I review what is known about seasonal changes in steroid hormone receptor abundance in relation to seasonal behaviour in vertebrates. I find that there is widespread, though not ubiquitous, seasonal variation in the expression of steroid hormone receptors in the brain, with such variation being best documented in association with courtship, mating and aggression. The most common pattern of seasonal variation is for there to be upregulation of sex steroid receptors with the expression of courtship and mating behaviours, when circulating hormone levels are also high. Less well-documented are cases in which seasonal increases in receptor expression could compensate for low circulating hormone levels or seasonal downregulation that could serve a protective function. I conclude by identifying important directions for future research.

Variation in chronotype is associated with migratory timing in a songbird.

Like many organisms, birds exhibit daily (circadian) and seasonal biological rhythms, and within populations both daily and seasonal timing often vary among individuals. Because photoperiod interacts with the circadian rhythms of many organisms to induce seasonal changes in behaviour and physiology, it is hypothesized that differences in daily timing, called chronotypes, underpin differences among individuals in the timing of seasonal events. For seasonal events stimulated by increasing daylength, this hypothesis predicts a positive relationship between the timing of daily and seasonal activities of individuals, with advanced chronotypes expressing events earlier in the year. The few previous tests of this hypothesis have focused on seasonal reproductive timing in birds. However, the hypothesis predicts that this relationship should extend to other photoinduced seasonal events. Therefore, we tested whether variation in chronotype was associated with variation in spring migratory timing in a captive songbird model, the pine siskin (Spinus pinus). We found that pine siskins expressing migratory restlessness exhibited repeatable chronotypes in their timing of nocturnal activity. Further, chronotype was significantly associated with the onset date of migratory behaviour, consistent with the hypothesized relationship between chronotype and seasonal timing.

Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects.

INTRODUCTION: The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk-benefit messaging when a safety signal is identified. DISCUSSION: The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll-out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high-quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. CONCLUSIONS: The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk-benefit trade-offs in a variety of contexts; guidance to transform this risk-benefit balance into effective and agreed-upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities.

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.

Declining food availability, corticosterone, and migratory response in a nomadic, irruptive migrant.

While obligate migrants time their movements to respond to predictable changes in the environment, facultative migration is characterized by more variable movements that are driven by unpredictable changes in resource availability. The proximate cues that trigger facultative migrations and the endocrine mechanisms involved in these responses remain poorly understood, though corticosterone may be a key mediator of facultative migration due to its effects on activity and metabolic processes. We conducted experiments in the fall and spring to examine the response of pine siskins (Spinus pinus), a facultative migrant, to a two-stage food restriction. Our goals were to examine whether declining food availability stimulated behavioral and/or physiological changes consistent with a migratory response, whether anticipatory behavioral and physiological adjustments occurred when birds were initially presented with changing food availability, and if observed changes corresponded to changes in circulating corticosterone levels. We found no evidence of preparatory physiological changes for migration, but food-restricted birds in the spring had increased daytime activity indicative of a migratory response. Corticosterone increased at each stage of the restriction and the change in corticosterone corresponded to the magnitude of decline in body condition. Increased corticosterone was also correlated with larger increases in activity during the initial stage of food restriction, but only during the spring, when birds also displayed higher levels of initial body condition. These results suggest that initial energetic state and corticosterone response may interact to determine an individual's behavioral and physiological response to declining food availability and ultimately the facultative migratory response.

Increasing photoperiod stimulates the initiation of spring migratory behaviour and physiology in a facultative migrant, the pine siskin.

The transition to a migratory state involves coordinated changes in physiology and behaviour. In species with regular, predictable (obligate) migrations, increasing day length triggers the expression of a spring migratory state and androgens play an important role in stimulating its development. By contrast, we know little about the environmental cues and endocrine mechanisms that regulate migration in species with less predictable (facultative) migrations. Here, we tested whether photoperiod stimulates a migratory state in a facultative nomadic migrant, the pine siskin (Spinus pinus). We exposed wintering birds to either a naturally increasing or short-day photoperiod and measured physiological and behavioural changes indicative of a migratory state. We also examined changes in circulating hormones that may play a role in the migratory transition. Natural-day, but not short-day, birds displayed physiological preparations for migration, including increases in fat deposition, and showed increased levels of migratory restlessness. We found no evidence for a role of corticosterone in the migratory transition, but testosterone may be important. This study is the first experimental test of the role of photoperiod in regulating facultative migration and demonstrates that the predictive cue used by many obligate migrants to time spring migration is also important in a facultative migrant.

Effects of temperature on the timing of breeding and molt transitions in house finches.

Temperature-correlated shifts in reproductive timing are now well documented in numerous bird species. However, whether temperature directly influences reproductive timing or whether its effects are mediated by an intermediate environmental cue, such as plant phenology, remains poorly understood. In this study, we investigated the direct effects of temperature on reproductive timing in house finches (Haemorhous mexicanus), which have a range and breeding diet not well represented in previous studies of temperature and reproductive timing. We conducted experiments with captive male house finches in which temperature was elevated within realistic ranges and the effects on the timing of preparations for reproduction, as well as on the termination of reproduction and the onset of prebasic feather molt, were examined. We found no adjustments in the timing of reproductive preparations of males in direct response to temperature. However, elevated temperature did advance the breeding-molt transition. Our results suggest that elevated temperatures in the range tested here do not directly impact physiological preparations for reproduction in male house finches, but may constrain the timing of the breeding-molt transition in this species.

Strategies for Identifying and Linking HIV-Infected Infants, Children, and Adolescents to HIV Treatment Services in Resource Limited Settings.

Many children living with HIV in resource-limited settings remain undiagnosed and at risk for HIV-related mortality and morbidity. This article describes 5 key strategies for strengthening HIV case finding and linkage to treatment for infants, children, and adolescents. These strategies result from lessons learned during the Accelerating Children's HIV/AIDS Treatment Initiative, a public-private partnership between the President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF). The 5 strategies include (1) implementing a targeted mix of HIV case finding approaches (eg, provider-initiated testing and counseling within health facilities, optimization of early infant diagnosis, index family testing, and integration of HIV testing within key population and orphan and vulnerable children programs); (2) addressing the unique needs of adolescents; (3) collecting and using data for program improvement; (4) fostering a supportive political and community environment; and (5) investing in health system-strengthening activities. Continued advocacy and global investments are required to eliminate AIDS-related deaths among children and adolescents.

Understanding variation in migratory movements: A mechanistic approach.

Spatial and temporal fluctuations in resource availability have led to the evolution of varied migration patterns. In order to appropriately time movements in relation to resources, environmental cues are used to provide proximate information for timing and the endocrine system serves to integrate these external cues and behavioral and physiological responses. Yet, the regulatory mechanisms underlying migratory timing have rarely been compared across a broad range of migratory patterns. First, we offer an updated nomenclature of migration using a mechanistic perspective to clarify terminology describing migratory types in relation to ecology, behavior and endocrinology. We divide migratory patterns into three types: obligate, nomadic, and fugitive. Obligate migration is characterized by regular and directed annual movements between locations, most commonly for breeding and overwintering, where resources are predictable and sufficient. Nomadic migrations occur less predictably than do obligate migrations as animals make use of potentially rich but ephemeral resources that occur unpredictably in space or time. Fugitive migrations move animals away from an area in response to severe disruption of environmental conditions and occur as part of an emergency life history stage. We also consider partially migratory populations, which include a mix of sedentary and migratory individuals; the movement patterns of partial migrants are expected to fall into one of the three types above. For these various forms of migration, we review our understanding of the environmental cues and endocrine mechanisms that underlie the expression of a migratory state. Several common hormonal mechanisms exist across the varied migratory forms, but there are also important areas where further investigations are needed in order to gain broad insight into the origin of movements and the diversity of migratory patterns. We propose that taking a comparative approach across the migratory types that considers endocrine mechanisms will advance a new understanding of migration biology.

Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials.

BACKGROUND: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials. METHODS: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation. RESULTS: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit. CONCLUSION: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.

Confronting Challenges in Monitoring and Evaluation: Innovation in the Context of the Global Plan Towards the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive.

The Global Plan Towards the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive (Global Plan), which was launched in 2011, set a series of ambitious targets, including a reduction of new HIV infections among children by 90% by 2015 (from a baseline year of 2009) and AIDS-related maternal mortality by 50% by 2015. To reach these targets, the Global Plan called for unprecedented investments in the prevention of mother-to-child transmission of HIV (PMTCT), innovative new approaches to service delivery, immense collective effort on the programmatic and policy fronts, and importantly, a renewed focus on data collection and use. We provide an overview of major achievements in monitoring and evaluation across Global Plan countries and highlight key challenges and innovative country-driven solutions using PMTCT program data. Specifically, we describe the following: (1) Uganda's development and use of a weekly reporting system for PMTCT using short message service technology that facilitates real-time monitoring and programmatic adjustments throughout the transition to a "treat all" approach for pregnant and breastfeeding women living with HIV (Option B+); (2) Uganda's work to eliminate parallel reporting systems while strengthening the national electronic district health information system; and (3) how routine PMTCT program data in Nigeria can be used to estimate HIV prevalence at the local level and address a critical gap in local descriptive epidemiologic data to better target limited resources. We also identify several ongoing challenges in data collection, analysis, and use, and we suggest potential solutions.