Natural Life History Research Articles

Differences in Gut Microbes Across Age and Sex Linked to Metabolism and Microbial Stability in a Hibernating Mammal.

The gut microbiome has a well-documented relationship with host fitness, physiology, and behavior. However, most of what is known comes from captive animals where diets and environments are more homogeneous or controlled. Studies in wild populations that experience dynamic environments and have natural life history variation are less common but are key to understanding the drivers of variation in the gut microbiome. Here we examine a wild population of yellow-bellied marmots (Marmota flaviventer), an obligate winter hibernator, to quantify multivariate associations between host-associated factors (e.g., age, sex, environmental harshness, and social behavior) and gut microbial composition. Across 5 years and 143 individuals, we found that males had a higher relative abundance of microbes associated with mass gain and cellulose digestion, which suggests a metabolic investment in mass gain (such as phylum Firmicutes and family Lachnospiraceae). By contrast, females had higher relative abundances of microbes associated with inflammation and metabolism (from microbial groups such as Tenericutes and Ruminococcus), possibly reflecting the importance of lactation and offspring investment. Post hoc analyses of lactating females showed a negative relationship with the abundance of microbes associated with mass gain but a positive relationship with microbes associated with metabolic energy, suggesting a trade-off between investment in pups and maternal mass gain. Older animals also had reduced Proteobacteria relative abundance, a phylum associated with reduced inflammation. Results demonstrate that sex and age-based traits, not sociality or environmental harshness, are associated with microbe-mediated metabolism and inflammation in a wild, hibernating mammal.

Health, economic and social burden of tobacco in Latin America and the expected gains of fully implementing taxes, plain packaging, advertising bans and smoke-free environments control measures: a modelling study

ObjectiveTo investigate the tobacco-attributable burden on disease, medical costs, productivity losses and informal caregiving; and to estimate the health and economic gains that can be achieved if the main tobacco...

Nature dependence and seasonality change perceptions for climate adaptation and mitigation

Global climate change is a scientifically demonstrated phenomenon, but there are discrepancies in societies about how people perceive it. People’s correct perceptions to climate change are necessary for their cooperative acts and behaviors toward adaptation and mitigation. While most research in this regard focuses on temporal trends of specific climate variables, e.g., temperature and rainfall, in relation to socio-demographic factors, few reports have systematically examined who perceive a change in climatic regularity and patterns, i.e., seasonality change. We hypothesize that people tend to perceive the seasonality change as their life practices and experiences are dependent on climate and nature. Interviews with 7 experts and surveys with 1011 respondents were conducted in the Meghna basin, Bangladesh, where the number of seasons in an annual calendar is reported to have decreased from six to four (Islam and Kotani, 2016). With the data, this research investigates people’s perceptions to seasonality change in relation to life practices, experiences and socioeconomic factors. The analysis shows that dependence on natural resources in the profession along with experiences of natural disasters and life history in the dwelling locations shape people’s correct perceptions to climate seasonality. This result suggests that people are not likely to realize the seasonality change as they are dwelling in urban areas with high mobility or as their life is detached from climate and nature, being neither willing nor cooperative to take adaptation and mitigation.

Seasonal variation of euphausiid life stage and taxonomic composition near the upwelling site northeast of Taiwan

Euphausiids are commercial fishery targets and one of the primary preys of an important component of marine food webs. However, knowledge about the natural life history of euphausiids in the East China Sea is limited. To describe the seasonal variation of euphausiids abundance, diversity, life stage, and taxonomic composition, we visited a site northeast of Taiwan (25.5°N, 121.9°E) in 21 cruises from May 2010 to September 2016. This site is known for an all-year-round upwelling due to the impingement of Kuroshio onto the continental shelf break. We found that the overall euphausiids abundance and diversity tended to be higher in summer to autumn (June to November) compared with spring. In terms of life stages, we found that larval stages (furcilia and calyptopis) predominated in spring when upwelling was prominent, while post-larval stages (juvenile and adult) dominated in summer and autumn when upwelling was weak, and stratification was strong. Moreover, we found that, in spring and summer, Euphausia nana was the dominant species accounting for 90% of total euphausiid abundance, whereas in autumn, Pseudeuphausia latifrons was the dominant species occupying 36% of total abundance. This study provides the foundation to better understand the ecological roles of euphausiids under the influences of upwelling northeast of Taiwan.

Book review of The lives of sharks: A natural history of shark life

Book review of <i>The lives of sharks: A natural history of shark life</i>

The concepts and origins of cell mortality

Organismal death is foundational to the evolution of life, and many biological concepts such as natural selection and life history strategy are so fashioned only because individuals are mortal. Organisms, irrespective of their organization, are composed of basic functional units—cells—and it is our understanding of cell death that lies at the heart of most general explanatory frameworks for organismal mortality. Cell death can be exogenous, arising from transmissible diseases, predation, or other misfortunes, but there are also endogenous forms of death that are sometimes the result of adaptive evolution. These endogenous forms of death—often labeled programmed cell death, PCD—originated in the earliest cells and are maintained across the tree of life. Here, we consider two problematic issues related to PCD (and cell mortality generally). First, we trace the original discoveries of cell death from the nineteenth century and place current conceptions of PCD in their historical context. Revisions of our understanding of PCD demand a reassessment of its origin. Our second aim is thus to structure the proposed origin explanations of PCD into coherent arguments. In our analysis we argue for the evolutionary concept of PCD and the viral defense-immunity hypothesis for the origin of PCD. We suggest that this framework offers a plausible account of PCD early in the history of life, and also provides an epistemic basis for the future development of a general evolutionary account of mortality.

5609968 REAL-WORLD PATIENT-REPORTED OUTCOMES AND WEARABLE METRIC CORRELATIONS: REMOTE DAILY MONITORING FOR EXPLORATION OF QUALITY OF LIFE IN SICKLE CELL DISEASE

Background/Aims: Sickle Cell Disease (SCD) is a debilitating condition that lacks data on its natural history and quality of life (QoL) beyond limited snapshots through infrequent healthcare contacts. This lack of longitudinal targeted QoL measurement and understanding of the physiological factors that may influence it sees a need for more detail on the impacts key metrics have on patient outcomes. The core objective of this study was to generate real-world evidence tracking changes in live wearable metrics and patient QoL, to better characterise a baseline of key correlations in SCD. Methods: Data was collected from 238 patients over 16 months, using a CE and FDA-cleared wearable (Withings ScanWatch) to automatically record metrics including sleep quality, activity, and heart rate. EQ-5D-5L and pain scores (0-10) were manually entered by patients via a digital patient-reported outcomes (PRO) portal, and a daily cohort average across each metric was calculated. Statistically significant correlations were analysed both at an overall day-to-day level and split by weekday vs. weekend to explore the potential impacts of activities such as work on sleep patterns. Patients provided informed e-consent to participate and for analysis of their de-identified data. Results: Increasing daily EQ-5D-5L scores were found to correlate with increasing numbers of sleep disturbances (p=0.024) and decreasing pain scores (p<0.001). In turn, lower pain scores were associated with lower sleep heart rates (p<0.001) and wake-up durations (p<0.001), as well as lower active heart rates (p<0.001) and higher activity levels (p<0.001).While sleep quality (sleep disturbances) appeared to show a contradictory increase with higher EQ-5D scores, the significance of this correlation was lost following a split by weekdays and weekends. Statistical significance was also lost for the link between pain scores and steps during the weekend, whereas an additional correlation between pain and total sleep duration (p=0.023) was found only during weekdays, and between pain and the number of sleep disturbances (p=0.033) during the weekend. Similarly, a correlation between EQ-5D and active heart rate (p=0.022), as well as duration to wakeup (p=0.017), was seen only during the weekend. Summary-Conclusion: Analysis of putative associations between PROs and real-time metrics, as well as the potential influences of activities such as work, were shown by changes in significance both before and after split by weekdays/weekends. Notably, lower EQ-5D scores were found to correlate with higher levels of pain, in turn linking to lower daily steps. With a correlating increase in both active and sleep heart rates despite these lower activity levels, this may indicate higher detectable stress correlating with increased pain, with paralleled impacts on QoL. As such, these metrics may form points of monitoring when identifying or predicting risks of pain and related complications in SCD patients. Future work will explore potential causality, differences across patient groups, and more granular detail of the impact of specific treatments or healthcare events. Additional investigation into changes at an individual patient level will be conducted to better characterise deviations from patients’ own baselines. This will support ongoing work to improve the understanding of baselines in SCD, and what the key factors in pain and quality of life may be in order to support patient outcomes improvement.

Nesting ecology and reproductive success of mixed-grass prairie songbirds

Vast areas of North American grasslands have been lost and degraded, resulting in unprecedented declines of biodiversity. For example, 82% of North American grassland songbird species are experiencing population declines. Basic natural history, life history, and demographic data from different regions and time periods are essential for modeling population dynamics and developing effective conservation strategies for grassland birds. We monitored 392 nests to provide information on nesting biology, quantify reproductive success, and gain insight into the extent to which predation and weather influence nest survival of 7 grassland songbird species in southwest Saskatchewan, during 2010 and 2011. Clutch sizes of all species were within the range reported previously and declined as the breeding season progressed, particularly for Chestnut-collared Longspur (Calcarius ornatus), Vesper (Pooecetes gramineus) and Baird's (Centronyx bairdii) sparrows, and Western Meadowlark (Sturnella neglecta). Overall, 32–69% of the nests we monitored were depredated, and predation accounted for 91% of all unsuccessful nesting attempts. Daily survival rates were lowest during the nestling stage for 5 species, and nest survival estimates ranged from 16% to 48%. Nest survival of 4 species was influenced by the temporal effects of age and date. Chestnut-collared Longspur and Western Meadowlark nest survival increased through early to mid-incubation and declined thereafter until ∼3 d prior to fledging before increasing again. Nest survival of these 2 species, along with Sprague's Pipit (Anthus spragueii) and Vesper Sparrow, were lowest in late June to early July. We found no support for a strong effect of precipitation on nest survival. However, nest survival rates declined with increasing ambient temperature for Chestnut-collared Longspur and Horned Lark (Eremophila alpestris), the 2 study species with the most exposed nests, and were highest for Western Meadowlark nests when ambient temperatures were between 15 and 24 °C.

Nesting ecology and reproductive success of mixed-grass prairie songbirds

Vast areas of North American grasslands have been lost and degraded, resulting in unprecedented declines of biodiversity. For example, 82% of North American grassland songbird species are experiencing population declines. Basic natural history, life history, and demographic data from different regions and time periods are essential for modeling population dynamics and developing effective conservation strategies for grassland birds. We monitored 392 nests to provide information on nesting biology, quantify reproductive success, and gain insight into the extent to which predation and weather influence nest survival of 7 grassland songbird species in southwest Saskatchewan, during 2010 and 2011. Clutch sizes of all species were within the range reported previously and declined as the breeding season progressed, particularly for Chestnut-collared Longspur (Calcarius ornatus), Vesper (Pooecetes gramineus) and Baird's (Centronyx bairdii) sparrows, and Western Meadowlark (Sturnella neglecta). Overall, 32–69% of the nests we monitored were depredated, and predation accounted for 91% of all unsuccessful nesting attempts. Daily survival rates were lowest during the nestling stage for 5 species, and nest survival estimates ranged from 16% to 48%. Nest survival of 4 species was influenced by the temporal effects of age and date. Chestnut-collared Longspur and Western Meadowlark nest survival increased through early to mid-incubation and declined thereafter until ∼3 d prior to fledging before increasing again. Nest survival of these 2 species, along with Sprague's Pipit (Anthus spragueii) and Vesper Sparrow, were lowest in late June to early July. We found no support for a strong effect of precipitation on nest survival. However, nest survival rates declined with increasing ambient temperature for Chestnut-collared Longspur and Horned Lark (Eremophila alpestris), the 2 study species with the most exposed nests, and were highest for Western Meadowlark nests when ambient temperatures were between 15 and 24 °C.

Clinical Trial Design for Disease-Modifying Therapies for Genetic Epilepsies.

Although trials with anti-seizure medications (ASMs) have not shown clear anti-epileptogenic or disease-modifying activity in humans to date, rapid advancements in genomic technology and emerging gene-mediated and gene replacement options offer hope for the successful development of disease-modifying therapies (DMTs) for genetic epilepsies. In fact, more than 26 potential DMTs are in various stages of preclinical and/or clinical development for genetic syndromes associated with epilepsy. The scope of disease-modification includes but is not limited to effects on the underlying pathophysiology, the condition's natural history, epilepsy severity, developmental achievement, function, behavior, sleep, and quality of life. While conventional regulatory clinical trials for epilepsy therapeutics have historically focused on seizure reduction, similarly designed trials may prove ill-equipped to identify these broader disease-modifying benefits. As we look forward to this pipeline of DMTs, focused consideration should be given to the challenges they pose to conventional clinical trial designs for epilepsy therapeutics. Just as DMTs promise to fundamentally alter how we approach the care of patients with genetic epilepsy syndromes, DMTs likewise challenge how we traditionally construct and measure the success of clinical trials. In the following, we briefly review the historical and preclinical frameworks for DMT development for genetic epilepsies and explore the many novel challenges posed for such trials, including the choice of suitable outcome measures, trial structure, timing and duration of treatment, feasible follow-up period, varying safety profile, and ethical concerns.

Benign paroxysmal torticollis: phenotype, natural history, and quality of life.

Benign paroxysmal torticollis (BPT) is characterized by attacks of head tilt associated with vomiting, irritability, and/or ataxia in early childhood. BPT is associated with migraine but risk factors are unknown. Impact on quality of life is also unknown. Parents/caregivers of children with ongoing or resolved BPT participated in telephone interviews (n = 73). Those with ongoing BPT completed the Infant Toddler Quality of Life questionnaire (ITQoL). Median age of children at the time of interview was 2.9 years (range 0.25-23). BPT was ongoing in 52% (n = 38). Nineteen percent (n = 14) developed migraine (median age 9.25 years, range 2.5-23) and 63% (n = 46) developed another episodic syndrome associated with migraine. Proportion of patients who developed migraine was higher among those with certain migrainous symptoms during BPT attacks vs. those without: phonophobia (58 vs. 21%, p = 0.02), photophobia and phonophobia (55 vs. 23%, p = 0.05), and photophobia, phonophobia, and motion sensitivity (60 vs. 22%, p = 0.02). ITQoL results showed significant impact of BPT on quality of life. Children with BPT may develop migraine or other episodic syndromes associated with migraine. Presence of migrainous features during BPT episodes may increase likelihood of developing migraine. Though characterized as "benign," BPT can significantly impact children and families. Benign paroxysmal torticollis (BPT) is a rare condition of early childhood characterized by episodes of head tilt associated with vomiting, irritability, ataxia, pallor, and/or malaise. This cohort study describes the phenotypic spectrum of BPT, variable treatment, natural history and association with migraine, and impact on development and quality of life. Children with BPT may go on to develop migraine or episodic syndromes that may be associated with migraine; presence of migrainous features during attacks may increase odds of developing migraine. BPT can have significant impact on quality of life, demonstrated by findings from the Infant Toddler Quality of Life questionnaire.

Natural History, Treatment Outcomes and Quality of Life in Idiopathic Normal Pressure Hydrocephalus (iNPH).

The natural history and treatment outcomes in adult patients with hydrocephalus is a broad and heterogeneous topic that encompasses the natural history of the various subtypes of adult hydrocephalus with or without treatment; their surgical operative results, including symptom improvements, treatment failure, short- and long-term complications, and reoperations; and morbidity, mortality, and patient-centered health-related quality of life (HRQoL). The objective of this review is to present a current update on the natural history and treatment outcomes, including QoL, for adults with hydrocephalus with a focus on patients with idiopathic normal pressure hydrocephalus (iNPH). A nonsystematic review of relevant literature was summarized. The natural history for untreated patients with iNPH is poor, with both increased mortality and morbidity. It is strongly recommended that practitioners follow established guidelines to select patients with suspected iNPH while using objective measures of gait, balance, and cognition for consideration of treatment with a CSF shunt. Other factors such as patient-related medical comorbidities or frailty may need to be factored into the decision-making process before surgical treatment is offered. As a rule, failure to select patients based on the identified guidelines will result in a significantly lower positive response to treatment with a CSF shunt. Over 90% of iNPH patients who undergo CSF-shunt treatment demonstrate symptomatic relief after surgery, and long-term studies have shown that in most patients, the clinical improvements are long-lasting, with over 70% demonstrating improvement longer than 6 years after treatment. There is no evidence to support the routine use of endoscopic third ventriculostomy (ETV) to treat patients with iNPH. There is limited data regarding HRQoL in patients with iNPH. In addition to objective measures of outcomes focused on gait and cognition, it is equally important for future studies to assess patient-centered subjective measures of HRQoL.

Uncertainty and sensitivity analyses of extinction probabilities suggest that adult female mortality is the weakest link for populations of tsetse (Glossina spp).

BackgroundA relatively simple life history allows us to derive an expression for the extinction probability of populations of tsetse, vectors of African sleeping sickness. We present the uncertainty and sensitivity analysis of the extinction probability, to offer key insights into factors affecting the control or eradication of tsetse populations.MethodsWe represent tsetse population growth as a branching process, and derive closed form estimates of population extinction from that model. Statistical and mathematical techniques are used to analyse the uncertainties in estimating extinction probability, and the sensitivity of the extinction probability to changes in input parameters representing the natural life history and vital dynamics of tsetse populations.ResultsFor fixed values of input parameters, the sensitivity of extinction probability depends on the baseline parameter values. Extinction probability is most sensitive to the probability that a female is inseminated by a fertile male when daily pupal mortality is low, whereas the extinction probability is most sensitive to daily mortality rate for adult females when daily pupal mortality, and extinction probabilities, are high. Global uncertainty and sensitivity analysis show that daily mortality rate for adult females has the highest impact on the extinction probability.ConclusionsThe high correlation between extinction probability and daily female adult mortality gives a strong argument that control techniques which increase daily female adult mortality may be the single most effective means of ensuring eradication of tsetse population.

Reproduction in female wild cattle: Influence of seasonality on ARTs

Wild cattle species, often considered less alluring than certain conservation-dependent species, have not attracted the same level of interest as the charismatic megafauna from the general public, private or corporate donors, and other funding agencies. Currently, most wild cattle populations are vulnerable or threatened with extinction. The implementation of reproductive technologies to maintain genetically healthy cattle populations in situ and ex situ has been considered for more than 30 years. Protocols developed for domestic cattle breeds have been used with some success in various wild cattle species. However, inherent differences in the natural life history of these species makes extrapolation of domestic cattle protocols difficult, and in some cases, minimally effective. Reproductive seasonality, driven by either photoperiod or nutritional resource availability, has significant influence on the success of assisted reproductive technologies (ARTs). This review focuses on the physiological processes that differ in breeding (ovulatory) and non-breeding (anovulatory) seasons in female cattle, and the potential methods used to overcome these challenges. Techniques to be discussed within the context of seasonality include: estrus synchronization and ovulation induction, ovarian superstimulation, artificial insemination (AI), multiple ovulation embryo transfer (MOET), and ovum pick-up (OPU) with in vitro fertilization (IVF) and embryo transfer (ET).

The turquoise killifish: a genetically tractable model for the study of aging

Lifespan is a remarkably diverse trait in nature, ranging from just hours in adult mayflies to hundreds of years in the Greenland shark and quahog clam. Great disparities in lifespan are often observed even among somewhat closely related species; for example, in the laboratory, wild-derived strains of the common house mouse have a maximum observed lifespan of approximately 6 years, while a similarly sized rodent, the naked mole rat, can live for over 30 years. Comparative biology of aging across the tree of life provides a tremendous opportunity for understanding the molecular and genetic basis underlying lifespan and aging. However, a lack of molecular and laboratory tools has limited the ability of researchers to take full advantage of the incredible diversity of aging phenotypes in nature. Recent developments in genomic technology have made it increasingly possible to study non-canonical model organisms for aging. One promising new genetic model organism amenable to a range of experimental interventions is the turquoise killifish (Nothobranchius furzeri). This fish species has a naturally short lifespan and undergoes a wide range of aging-related transformations. These fish have a fully sequenced genome and transcriptome, and killifish embryos are accessible to transgenesis and genome editing. Furthermore, different killifish species and populations show striking differences in lifespan, providing the opportunity for comparative analysis of aging. This Review introduces the natural life history of the turquoise killifish, its emerging applicability as an aging model system, the genetic tools that have been developed to study aging for this species and a summary of recent studies facilitated by these new tools.

Burden of smoking in Brazil and potential benefit of increasing taxes on cigarettes for the economy and for reducing morbidity and mortality.

The prevalence of smoking in Brazil has decreased considerably in recent decades, but the country still has a high burden of disease associated with this risk factor. The study aimed to estimate the burden of mortality, morbidity, and costs for society associated with smoking in 2015 and the potential impact on health outcomes and the economy based on price increases for cigarettes through taxes. Two models were developed: the first is a mathematical model based on a probabilistic microsimulation of thousands of individuals using hypothetical cohorts that considered the natural history, costs, and quality of life of these individuals. The second is a tax model applied to estimate the economic benefit and health outcomes in different price increase scenarios in 10 years. Smoking was responsible for 156,337 deaths, 4.2 million years of potential life lost, 229,071 acute myocardial infarctions, 59,509 strokes, and 77,500 cancer diagnoses. The total cost was BRL 56.9 billion (USD 14.7 billion), with 70% corresponding to the direct cost associated with healthcare and the rest to indirect cost due to lost productivity from premature death and disability. A 50% increase in cigarette prices would avoid 136,482 deaths, 507,451 cases of cardiovascular diseases, 64,382 cases of cancer, and 100,365 cases of stroke. The estimated economic benefit would be BRL 97.9 billion (USD 25.5 billion). In conclusion, the burden of disease and economic losses associated with smoking is high in Brazil, and tax increases are capable of averting deaths, illness, and costs to society.

Burden of disease attributable to tobacco use in Paraguay, and potential health and financial impact of increasing prices through taxing

To consider the burden of disease associated to tobacco consumption in Paraguay and to evaluate the potential economic and health effect of price increase through taxes. A Monte Carlo simulation model was designed incorporating natural history, costs, and quality of life of diseases associated to smoking for 2015. Also, several scenarios were considered for the impact of tax raises on the prevalence of smoking and fiscal collection. In Paraguay, 3,354 people die every year as a consequence of smoking. Nineteen percent of deaths are due to cardiac ischemia, 15% due to stroke. 77% of deaths due to chronic obstructive pulmonary disease (COPD), and 83% of lung cancer can be attributed to smoking. These diseases in Paraguay represent an annual direct medical cost of more than 1.5 trillion PYG, while the tax collection from cigarette sales barely covers 20% of this expense. A 50% increase in the price of cigarettes via taxes could avoid 2507 deaths in ten years and generate resources by 2.4 trillion in savings in health expenses and tax of collection. The cost and the burden of disease associated to tobacco consumption is high in the health system in Paraguay. An increase in cigarette price through taxes could have significant health benefits and could offset health costs in part.

Observations of Wood Turtle Activity, Diet, Movements, and Morphometrics in the Central Appalachians

Glyptemys insculpta (Wood Turtle) populations are declining as habitat is developed and individuals are collected for the pet trade. Information about the natural history and life history of the species can help inform conservation strategies, especially for populations about which little information is currently available. Because basic ecological information is lacking for populations in the Central Appalachians, we studied the natural history of Wood Turtles in West Virginia from 2009 to 2011. Wood Turtle males were larger than females in carapace length and width, bridge height, and mass. Turtles were primarily terrestrial in spring and summer and aquatic in autumn and winter. Aquatic mating was most prevalent in autumn. Nesting attempts, which were mostly in sandy substrates, were made in spring during early morning and evening. Slugs made up the majority (67%) of the turtles' diet, although other invertebrates, vertebrate remains, berries, and green leaves were also consumed. In autumn, turtles entered the river for brumation. This study adds to our understanding of the natural history of Wood Turtles near the southern extent of their range.

Systematic Review: The Epidemiology, Natural History, and Burden of Alagille Syndrome.

ABSTRACTBackground and Aim:Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death. The aim of the study was to perform the first systematic review of the epidemiology, natural history, and burden of ALGS with a focus on the liver component.Methods:Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health-related quality of life (HRQoL) outcomes in patients with ALGS.Results:Of 525 screened publications, 20 met the inclusion criteria. Liver-related features included cholestasis (87%–100% of patients), jaundice (66%–85%), and cirrhosis (44%–95%). Between 15% and 47% of patients underwent liver transplantation and 4% to 14% received partial biliary diversion. Pruritus affected the majority of patients (59%–88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS.Conclusions:Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease-specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL.

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospectivestudies of low-risk tumors suitable for active surveillance.