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Changes in phenology are a common response to climate change, but their impact on population dynamics is often ambiguous and at‐risk species are omitted from most analyses.We assessed the relationship between change in abundance and change in phenology for 114 butterfly populations of 31 at‐risk species from five families in 10 US states. We used data from Pollard‐walk and similar monitoring programmes for which count data were collected on multiple occasions per year. We also collected information from managers on site‐level management interventions.To estimate abundance, we first fit separate smoothing splines for each species at each site. Yearly abundance was estimated as the area under the activity curve for that year, and from this, we estimated abundance trends over the period for which we had population data. Phenological shifts were measured as the changes in median activity date, beginning of flight season, duration of flight season and phenological constancy (negative of the magnitude of trends in median activity date). We also evaluated the association of ecological traits (voltinism, diet breadth, position within geographic range, ecoregion, overwintering stage and seasonality) and management (proportion of years with interventions) with trends in abundance and in phenology.Across all populations, the estimated trend in abundance was −0.085, equivalent to an 8.1% decline/year. Positive trends in abundance were associated with smaller shifts in the median flight date (higher constancy). We also found strong associations between trends in abundance and management interventions, with increased management associated with increasing abundance trends. In general, ecological traits were not strongly associated with trends in phenology or trends in abundance.Synthesis and applications: Populations with less phenological constancy are more likely to be rapidly declining and populations with more frequent management interventions are increasing. These results suggest that one key outcome of management interventions may be to mitigate some of the impacts of climate change, which in turn may contribute to higher population growth. These results also imply that managers may need to alter the timing of appropriate management to synchronize with activities of at‐risk species as species shift their phenology. [ABSTRACT FROM AUTHOR]

Background: Frailty is characterised by a decline in physical, cognitive, energy, and health reserves and is linked to greater functional dependency and higher social care utilisation. However, the relationship between receiving care, or receiving insufficient care among older people with different frailty status and the risk of unplanned admission to hospital for any cause, or the risk of falls and fractures remains unclear. Methods and findings: This study used information from 7,656 adults aged 60 and older participating in the English Longitudinal Study of Ageing (ELSA) waves 6–8. Care status was assessed through received care and self-reported unmet care needs, while frailty was measured using a frailty index. Competing-risk regression analysis was used (with death as a potential competing risk), adjusted for demographic and socioeconomic confounders. Around a quarter of the participants received care, of which approximately 60% received low levels of care, while the rest had high levels of care. Older people who received low and high levels of care had a higher risk of unplanned admission independent of frailty status. Unmet need for care was not significantly associated with an increased risk of unplanned admission compared to those receiving no care. Older people in receipt of care had an increased risk of hospitalisation due to falls but not fractures, compared to those who received no care after adjustment for covariates, including frailty status. Conclusions: Care receipt increases the risk of hospitalisation substantially, suggesting this is a group worthy of prevention intervention focus. [ABSTRACT FROM AUTHOR]

Background: The use of electronic cigarettes (e-cigarette) offers potential to facilitate cigarette smoking cessation, yet potentially increases risk of cigarette smoking initiation. This relationship has been primarily modeled in mathematical ways that often do not represent real-world complexities, which could inform decisions regarding local prevention programs or policies. Aims: To develop a model of cigarette and e-cigarette use that combines current research on tobacco use and incorporates real-world geographic and demographic data. Method: We used a platform for developing agent-based models with demographic information representative of the population in Pennsylvania. We developed three models of cigarette and e-cigarette use. The primary outcome for each was the total number of users for cigarette, e-cigarette, and total nicotine. The first model applied current cigarette and e-cigarette data, the second tested the effect of implementing a program of e-cigarette education and policies, and the third considered a social contagion factor, where local schools functioned as a transmission vector. Results: The baseline and social contagion models found an overall decline in cigarette use but an increase in e-cigarette and total nicotine use. The education/policies model had declines in all categories. Sensitivity analysis suggested the importance of nuanced e-cigarette/cigarette interactions when modeling tobacco use. Discussion: Public health campaigns that focus on reducing youth e-cigarette usage can have a large effect. Social contagion should be strongly considered when studying e-cigarette spread. Conclusion: Targeted public health campaigns focused on reducing school prevalence of e-cigarette use may be particularly valuable.

The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy.sup.1. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood.sup.2. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures. A new age-period-cohort analysis reveals distinct generational patterns in deaths from opioid overdose in the United States, suggesting increased risks for Baby Boomers and Millennials., Author(s): Hawre Jalal [sup.1] , Jeanine M. Buchanich [sup.2] , David R. Sinclair [sup.1] [sup.3] , Mark S. Roberts [sup.1] , Donald S. Burke [sup.4] Author Affiliations: (1) Department of [...]

Unexploded ordnance (UXO), often deployed in WWI and WWII, are still present on the seabed posing a risk to seabed construction. UXO surveys identify potential UXO targets which are then investigated and removed where necessary; however, approximately 96 per cent of targets investigated on projects included in this study were non-UXO (false positives). Here we investigate methods of improving statistical confidence in targets picked through the improved classification of magnetic response, utilizing simulation methods and historic data. A simulation of the induced magnetism of UXO was developed to model the most likely dimensions and orientation of a given source item. Modelling results and measured variables were combined in an optimization algorithm, hereon referred to as 'the classifier'. We document the results of integrating the magnetic responses of 3027 targets from 18 offshore wind projects into the classifier. Five of these projects were performed as tests in which the target results were unknown during classification. Finally, the classifier was deployed on a live project, Hollandse Kust Zuid 3 and 4 Offshore Wind Farm, in which it enabled the removal of 67 targets from the from the 1200-target investigation list. The classifier proved to be a valuable additional tool to assist the target rationalization process, reliably and repeatably distinguishing UXO from other items, thereby reducing false positives and repeatably demonstrating no threshold UXO false negatives. Assumptions and limitations of this methodology were highlighted, which must be understood and considered when integrating this approach on future projects. [ABSTRACT FROM AUTHOR]

Background: In 2005, we reported 3 patients with bilateral optic nerve damage early in life. These patients had stable vision for decades but then experienced significant bilateral vision loss with no obvious cause. Our hypothesis, novel at that time, was that the late decline of vision was due to age-related attrition of retinal ganglion cells superimposed on a reduced neuronal population due to the earlier injury. Evidence Acquisition: The field of epigenetics provides a new paradigm with which to consider the normal aging process and the impact of neuronal injury, which has been shown to accelerate aging. Late-in-life decline in function after early neuronal injury occurs in multiple sclerosis due to dysregulated inflammation and postpolio syndrome. Recent studies by our group in mice have also demonstrated the possibility of partial reversal of cellular aging and the potential to mitigate anatomical damage after injury and even improve visual function. Results: The results in mice and nonhuman primates published elsewhere have shown enhanced neuronal survival and visual function after partial epigenetic reprogramming. Conclusions: Injury promotes epigenetic aging , and this finding can be observed in several clinically relevant scenarios. An understanding of the epigenetic mechanisms at play opens the opportunity to restore function in the nervous system and elsewhere with cellular rejuvenation therapies. Our earlier cases exemplify how reconsideration of previously established concepts can motivate inquiry of new paradigms. [ABSTRACT FROM AUTHOR]

Background A growing number of older people provide unpaid care, but contemporary research evidence on this group is limited. Aim This study aims to describe the characteristics of older people who provide unpaid care and how these vary by socioeconomic position. Methods Using recent information from the English Longitudinal Study of Ageing (ELSA wave 9, 2019), we analysed cross-sectional data on 1,282 unpaid carers aged ≥50. Data on sociodemographics, health, social wellbeing, care intensity and caregiver–recipient relationships were extracted. Total net non-pension wealth quintiles were used as a relative measure of socioeconomic position. Differences between the poorest and richest wealth quintiles were examined through logistic regression. Findings Most older carers in ELSA were female and looking after another older person. Poor mental and physical health and social isolation were common, and socially patterned. Compared with carers in the middle wealth group, the poorest group were more likely to be living with the person they cared for (odds ratio (OR) 1.56 [95% confidence interval (CI) 1.03–2.36]) and more likely to experience loneliness (OR 2.29 [95% CI 1.42–3.69]), dependency (i.e. the need for help with activities of daily living) (OR 1.62 [95% CI 1.05–2.51]), chronic pain (OR 1.81 [95% CI 1.23–2.67]), a higher number of diseases (OR 1.75 [95% CI 1.15–2.65]) and fair/poor self-rated health (OR 2.59 [95% CI 1.79–3.76]). The poorest carers were also less likely to have a high quality of life (OR 0.51 [95% CI 0.33–0.80]) or be in work (OR 0.33 [95% CI 0.19–0.59]). Conclusion Our findings suggest that financially disadvantaged unpaid carers (and their households) may have the greatest needs for intervention and support. Focussing resources on this group has potential to address social inequalities. [ABSTRACT FROM AUTHOR]

Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases. [ABSTRACT FROM AUTHOR]

The NAD+‐dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late‐life health and overall lifespan, though of these members, a role for sirtuin‐2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under‐expressed. Here, we sought to test whether SIRT2 over‐expression would impact the overall health and lifespan of mice on a nonprogeroid, wild‐type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high‐fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2‐Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity. [ABSTRACT FROM AUTHOR]

It is unclear whether polypharmacy is associated with difficulty taking medications amongst people aged ≥85 living at home. This is despite the projected decline in availability of family carers, who may support independent living. Using Newcastle 85+ Study data and mixed‐effects modelling, we investigated the association between polypharmacy and difficulty taking medications amongst 85‐year‐olds living at home, over a 10‐year time period. Polypharmacy was not associated with difficulty taking medications as either a continuous (OR = 0.99 [0.91–1.08]) or categorical variable (5–9 medications, OR = 0.69 [0.34–1.41]; ≥10 medications, OR = 0.85 [0.34–2.07]). The significant predictors included disability, visual impairment and cognitive impairment. Our results suggest that people aged ≥85 living at home with disability, visual impairment and/or cognitive impairment will have difficulty taking their medications, regardless of how many they are prescribed. Therefore, healthcare professionals should routinely ask about, assess and address problems that these patient groups may have with taking their medicines, independent of the number of drugs taken. [ABSTRACT FROM AUTHOR]

The nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age‐related disease, whereby it is assumed that NMN is incorporated into NAD+ through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome. [ABSTRACT FROM AUTHOR]

Reduced expression of the NAD+-dependent deacetylase, SIRT3, has been associated with insulin resistance and metabolic dysfunction in humans and rodents. In this study, we investigated whether specific overexpression of SIRT3 in vivo in skeletal muscle could prevent high-fat diet (HFD)-induced muscle insulin resistance. To address this, we used a muscle-specific adeno-associated virus (AAV) to overexpress SIRT3 in rat tibialis and extensor digitorum longus (EDL) muscles. Mitochondrial substrate oxidation, substrate switching and oxidative enzyme activity were assessed in skeletal muscles with and without SIRT3 overexpression. Muscle-specific insulin action was also assessed by hyperinsulinaemic–euglycaemic clamps in rats that underwent a 4-week HFD-feeding protocol. Ex vivo functional assays revealed elevated activity of selected SIRT3-target enzymes including hexokinase, isocitrate dehydrogenase and pyruvate dehydrogenase that was associated with an increase in the ability to switch between fatty acid- and glucose-derived substrates in muscles with SIRT3 overexpression. However, during the clamp, muscles from rats fed an HFD with increased SIRT3 expression displayed equally impaired glucose uptake and insulin-stimulated glycogen synthesis as the contralateral control muscle. Intramuscular triglyceride content was similarly increased in the muscle of high-fat-fed rats, regardless of SIRT3 status. Thus, despite SIRT3 knockout (KO) mouse models indicating many beneficial metabolic roles for SIRT3, our findings show that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats. [ABSTRACT FROM AUTHOR]