Only rare classical MHC-I alleles are highly expressed in the European house sparrow.

The exceptional polymorphism observed within genes of the major histocompatibility complex (MHC), a core component of the vertebrate immune system, has long fascinated biologists. The highly polymorphic classical MHC class-I (MHC-I) genes are maintained by pathogen-mediated balancing selection (PMBS), as shown by many sites subject to positive selection, while the more monomorphic non-classical MHC-I genes show signatures of purifying selection. In line with PMBS, at any point in time, rare classical MHC alleles are more likely than common classical MHC alleles to confer a selective advantage in host-pathogen interactions. Combining genomic and expression data from the blood of wild house sparrows Passer domesticus, we found that only rare classical MHC-I alleles were highly expressed, while common classical MHC-I alleles were lowly expressed or not expressed. Moreover, highly expressed rare classical MHC-I alleles had more positively selected sites, indicating exposure to stronger PMBS, compared with lowly expressed classical alleles. As predicted, the level of expression was unrelated to allele frequency in the monomorphic non-classical MHC-I alleles. Going beyond previous studies, we offer a fine-scale view of selection on classical MHC-I genes in a wild population by revealing differences in the strength of PMBS according to allele frequency and expression level.

Interactive effects of rising temperatures and urbanisation on birds across different climate zones: A mechanistic perspective.

Climate change and urbanisation are among the most pervasive and rapidly growing threats to biodiversity worldwide. However, their impacts are usually considered in isolation, and interactions are rarely examined. Predicting species' responses to the combined effects of climate change and urbanisation, therefore, represents a pressing challenge in global change biology. Birds are important model taxa for exploring the impacts of both climate change and urbanisation, and their behaviour and physiology have been well studied in urban and non-urban systems. This understanding should allow interactive effects of rising temperatures and urbanisation to be inferred, yet considerations of these interactions are almost entirely lacking from empirical research. Here, we synthesise our current understanding of the potential mechanisms that could affect how species respond to the combined effects of rising temperatures and urbanisation, with a focus on avian taxa. We discuss potential interactive effects to motivate future in-depth research on this critically important, yet overlooked, aspect of global change biology. Increased temperatures are a pronounced consequence of both urbanisation (through the urban heat island effect) and climate change. The biological impact of this warming in urban and non-urban systems will likely differ in magnitude and direction when interacting with other factors that typically vary between these habitats, such as resource availability (e.g. water, food and microsites) and pollution levels. Furthermore, the nature of such interactions may differ for cities situated in different climate types, for example, tropical, arid, temperate, continental and polar. Within this article, we highlight the potential for interactive effects of climate and urban drivers on the mechanistic responses of birds, identify knowledge gaps and propose promising future research avenues. A deeper understanding of the behavioural and physiological mechanisms mediating species' responses to urbanisation and rising temperatures will provide novel insights into ecology and evolution under global change and may help better predict future population responses.

Thermoregulatory costs of the innate immune response are modulated by winter food availability in a small passerine.

In winter, a challenge to the immune system could pose a major energetic trade-off for small endotherms, whereby increasing body temperature (Tb ; i.e. eliciting fever) may be beneficial to fight off invading pathogens yet incur a cost for vital energy-saving mechanisms. Having previously shown that the availability and acquisition of energy, through manipulation of food predictability, influences the depth of rest-phase hypothermia in a wild bird in winter, we expected that the nocturnal thermoregulatory component of the acute-phase immune response would also be modulated by food availability. By manipulating winter food availability in the wild for great tits Parus major, we created an area offering a "predictable" and constant supply of food at feeding stations, while an unmanipulated area was subject to naturally "unpredictable" food. Birds were subject to an immune challenge shortly after dusk, and the thermoregulatory response was quantified via continuous recording of nocturnal Tb , using subcutaneous thermo-sensitive transponders. In response to immune challenge, all birds increased Tb above the level maintained prior to immune challenge (i.e. baseline). However, birds experiencing a naturally unpredictable food supply elevated Tb more than birds subject to predictable food resources, during the period of expected peak response and for the duration of the night. Furthermore, "unpredictable-food" females took longer to return to their baseline Tb . Assuming baseline nocturnal Tb reflects an individual's optimum, based on their available energy budget, the metabolic cost of eliciting an acute-phase response for "unpredictable-food" birds was more than double that of "predictable-food" birds. The absence of differences in absolute Tb during the peak response could support the idea of an optimal Tb for immune system activation. Alternatively, "predictable-food" birds could have acquired tolerance to endotoxin as a result of using feeding stations, thus affording them reduced costs associated with a smaller Tb increase. These findings shed new light on the trade-offs associated with food acquisition, thermoregulation and immune function in small-bodied endotherms. This knowledge is of increasing importance, given the predicted elevated pathogen risks associated with changes in climate and anthropogenic activities.

Urbanisation impacts plumage colouration in a songbird across Europe: Evidence from a correlational, experimental and meta-analytical approach.

Urbanisation is accelerating across the globe, transforming landscapes, presenting organisms with novel challenges, shaping phenotypes and impacting fitness. Urban individuals are claimed to have duller carotenoid-based colouration, compared to their non-urban counterparts, the so-called 'urban dullness' phenomenon. However, at the intraspecific level, this generalisation is surprisingly inconsistent and often based on comparisons of single urban/non-urban populations or studies from a limited geographical area. Here, we combine correlational, experimental and meta-analytical data on a common songbird, the great tit Parus major, to investigate carotenoid-based plumage colouration in urban and forest populations across Europe. We find that, as predicted, urban individuals are paler than forest individuals, although there are large population-specific differences in the magnitude of the urban-forest contrast in colouration. Using one focal region (Malmö, Sweden), we reveal population-specific processes behind plumage colouration differences, which are unlikely to be the result of genetic or early-life conditions, but instead a consequence of environmental factors acting after fledging. Finally, our meta-analysis indicates that the urban dullness phenomenon is well established in the literature, for great tits, with consistent changes in carotenoid-based plumage traits, particularly carotenoid chroma, in response to anthropogenic disturbances. Overall, our results provide evidence for uniformity in the 'urban dullness' phenomenon but also highlight that the magnitude of the effect on colouration depends on local urban characteristics. Future long-term replicated studies, covering a wider range of species and feeding guilds, will be essential to further our understanding of the eco-evolutionary implications of this phenomenon.

Urban tree composition is associated with breeding success of a passerine bird, but effects vary within and between years.

Birds breeding in urban environments have lower reproductive output compared to rural conspecifics, most likely because of food limitation. However, which characteristics of urban environments may cause this deficiency is not clear. Here, we investigated how tree composition within urban territories of passerine birds is associated with breeding probability and reproductive success. We used 7 years of data of breeding occupancy for blue and great tits (Cyanistes caeruleus; Parus major) and several reproductive traits for great tits, from 400 urban nest boxes located in 5 parks within the city of Malmö, Sweden. We found that tits, overall, were less likely to breed in territories dominated by either non-native trees or beech trees. Great tit chicks reared in territories dominated by non-native trees weighed significantly less, compared to territories with fewer non-native trees. An earlier onset of breeding correlated with increased chick weight in great tits. Increasing number of common oak trees (Quercus robur) was associated with delayed onset of breeding in great tits. Notably, as offspring survival probability generally increased by breeding earlier, in particular in oak-dominated territories, our results suggest that delayed onset of breeding induced by oak trees may be maladaptive and indicate a mismatch to this food source. Our results demonstrate that tree composition may have important consequences on breeding success of urban birds, but some of these effects are not consistent between years, highlighting the need to account for temporal effects to understand determinants of breeding success and inform optimal management in urban green spaces.

Morphine versus methadone for neonatal opioid withdrawal syndrome: a randomized controlled pilot study.

BACKGROUND: Neonatal Opioid Withdrawal Syndrome (NOWS) is a significant public health issue and while millions of neonates are affected each year, an optimal pharmacologic weaning protocol has yet to be demonstrated. In this study, we compare hospital length of stay (LOS) and length of treatment (LOT) for treatment of neonatal opioid withdrawal (NOWS) with morphine versus methadone. METHODS: This was a single-site, open-label, randomized controlled pilot study conducted from October 2016-September 2018. Infants were eligible if their primary in-utero drug exposure was heroin, oral opioids, or methadone and they were born at greater than or equal to 34 weeks gestation. Infants were excluded for serious medical comorbidities and primary in-utero exposure to buprenorphine. RESULTS: Sixty-one infants were enrolled; 30 were randomized to methadone treatment, and 31 to morphine treatment. Overall 46% of infants required treatment for NOWS. LOS and LOT for infants treated with morphine was 17.9 days and 14.7 days respectively, compared to 16.1 days and 12.8 days for babies treated with methadone (p = 0.5, p = 0.54). Infants treated with morphine received lower total morphine equivalents than those treated with methadone (9.7 vs. 33, p < 0.01). Three treated infants in the methadone group required transfer to the Neonatal Intensive Care Unit, versus no infants in the morphine group. CONCLUSIONS: Infants treated with morphine versus methadone had no significant differences in LOS or LOT in this pilot study. Infants treated with methadone received up to 3 times the opioid based on morphine equivalents as infants treated with morphine and had more transfers to the NICU for over sedation. CLINICAL TRIAL REGISTRATION: Morphine Versus Methadone for Opiate Exposed Infants With Neonatal Abstinence Syndrome NCT02851303 , initiated 01/08/2016.

Exposure to artificial light at night alters innate immune response in wild great tit nestlings.

The large-scale impact of urbanization on wildlife is rather well documented; however, the mechanisms underlying the effects of urban environments on animal physiology and behaviour are still poorly understood. Here, we focused on one major urban pollutant - artificial light at night (ALAN) - and its effects on the capacity to mount an innate immune response in wild great tit (Parus major) nestlings. Exposure to ALAN alters circadian rhythms of physiological processes, by disrupting the nocturnal production of the hormone melatonin. Nestlings were exposed to a light source emitting 3 lx for seven consecutive nights. Subsequently, nestlings were immune challenged with a lipopolysaccharide injection, and we measured haptoglobin and nitric oxide levels pre- and post-injection. Both haptoglobin and nitric oxide are important markers for innate immune function. We found that ALAN exposure altered the innate immune response, with nestlings exposed to ALAN having lower haptoglobin and higher nitric oxide levels after the immune challenge compared with dark-night nestlings. Unexpectedly, nitric oxide levels were overall lower after the immune challenge than before. These effects were probably mediated by melatonin, as ALAN-treated birds had on average 49% lower melatonin levels than the dark-night birds. ALAN exposure did not have any clear effects on nestling growth. This study provides a potential physiological mechanism underlying the documented differences in immune function between urban and rural birds observed in other studies. Moreover, it gives evidence that ALAN exposure affects nestling physiology, potentially causing long-term effects on physiology and behaviour, which ultimately can affect their fitness.

Predictability of food supply modulates nocturnal hypothermia in a small passerine.

The combination of short days and long cold winter nights, in temperate regions, presents a major challenge for small diurnal birds. Small birds regularly employ heterothermy and enter rest-phase hypothermia during winter nights to conserve energy. However, we know little about how environmental conditions, such as food availability, shape these strategies. We experimentally manipulated food availability in winter to free-living great tits Parus major. A 'predictable' and constant food supply was provided to birds in one area of a forest, while birds in another area did not have access to a reliable supplementary food source. We found that predictability of food affected the extent of nocturnal hypothermia, but the response differed between the sexes. Whereas male nocturnal body temperature was similar regardless of food availability, females exposed to a naturally 'unpredictable' food supply entered deeper hypothermia at night, compared with females that had access to predictable food and compared with males in both treatment groups. We suggest that this response is likely a consequence of dominance, and subdominant females subject to unpredictable food resources cannot maintain sufficient energy intake, resulting in a higher demand for energy conservation at night.

Waveguide-Integrated, Plasmonic Enhanced Graphene Photodetectors.

We present a micrometer-scale, on-chip integrated, plasmonic enhanced graphene photodetector (GPD) for telecom wavelengths operating at zero dark current. The GPD is designed to directly generate a photovoltage by the photothermoelectric effect. It is made of chemical vapor deposited single layer graphene, and has an external responsivity ∼12.2 V/W with a 3 dB bandwidth ∼42 GHz. We utilize Au split-gates to electrostatically create a p-n-junction and simultaneously guide a surface plasmon polariton gap-mode. This increases the light-graphene interaction and optical absorption and results in an increased electronic temperature and steeper temperature gradient across the GPD channel. This paves the way to compact, on-chip integrated, power-efficient graphene based photodetectors for receivers in tele- and datacom modules.

Revisited: A Systematic Review of Therapeutic Hypothermia for Adult Patients Following Traumatic Brain Injury.

OBJECTIVES: Therapeutic hypothermia has been of topical interest for many years and with the publication of two international, multicenter randomized controlled trials, the evidence base now needs updating. The aim of this systematic review of randomized controlled trials is to assess the efficacy of therapeutic hypothermia in adult traumatic brain injury focusing on mortality, poor outcomes, and new pneumonia. DATA SOURCES: The following databases were searched from January 1, 2011, to January 26, 2018: Cochrane Central Register of Controlled Trial, MEDLINE, PubMed, and EMBASE. STUDY SELECTION: Only foreign articles published in the English language were included. Only articles that were randomized controlled trials investigating adult traumatic brain injury sustained following an acute, closed head injury were included. Two authors independently assessed at each stage. DATA EXTRACTION: Quality was assessed using the Cochrane Collaboration's tool for assessing the risk of bias. All extracted data were combined using the Mantel-Haenszel estimator for pooled risk ratio with 95% CIs. p value of less than 0.05 was considered statistically significant. All statistical analyses were conducted using RevMan 5 (Cochrane Collaboration, Version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). DATA SYNTHESIS: Twenty-two studies with 2,346 patients are included. Randomized controlled trials with a low risk of bias show significantly more mortality in the therapeutic hypothermia group (risk ratio, 1.37; 95% CI, 1.04-1.79; p = 0.02), whereas randomized controlled trials with a high risk of bias show the opposite with a higher mortality in the control group (risk ratio, 0.70; 95% CI, 0.60-0.82; p < 0.00001). CONCLUSIONS: Overall, this review is in-keeping with the conclusions published by the most recent randomized controlled trials. High-quality studies show no significant difference in mortality, poor outcomes, or new pneumonia. In addition, this review shows a place for fever control in the management of traumatic brain injury.

Maternally derived yolk antioxidants buffer the developing avian embryo against oxidative stress induced by hyperoxia.

In oviparous animals, maternally transferred antioxidants protect the embryo from oxidative damage from high rates of reactive oxygen species (ROS) production incurred by rapid growth. Elevated ROS exposure, beyond that incurred by normal growth, can occur as a result of exposure to exogenous factors (e.g. pollutants, toxins, radiation), increasing the risk of oxidative damage, with potentially adverse consequences for embryonic development and long-term fitness. The capacity of the avian embryo's antioxidant protection system to counter an increased exogenous oxidative threat is poorly understood. We induced an external oxidative challenge via experimental increase in ambient oxygen concentration throughout incubation of wild great tit Parus major eggs in the laboratory. At day 11 of incubation, brain tissue revealed no consistent differences in oxidative stress status [as measured by antioxidant levels (superoxide dismutase and total glutathione), lipid peroxidation and telomere length] between control (21% oxygen) and hyperoxic (40% oxygen) embryos. However, the level of vitamin E was significantly lower and lipid peroxidation was significantly higher in yolks of eggs reared under elevated oxygen concentrations. The results suggest that maternally derived yolk antioxidants successfully buffer developing embryonic tissues against an increased exogenous oxidative threat. Furthermore, vitamin E plays a more important role in protecting the embryo than carotenoids. However, the depletion of antioxidants and increased peroxidation of lipids in the yolk could have negative consequences for embryonic development, in particular for the brain and heart that require highly unsaturated fatty acids, and protection against the oxidative burst following hatching.

Selective disappearance of great tits with short telomeres in urban areas.

Urban environments pose novel challenges, as well as opportunities, for urban-dwelling wildlife. Although differences have been reported in several phenotypic traits (e.g. morphology, physiology and behaviour) between urban and rural populations, it is poorly understood whether this affects individual fitness. Telomere dynamics are posited as one possible mechanism underlying senescence and mortality. It was recently shown that telomere shortening is accelerated when growing up in an urban, compared with a rural, environment. However, the implications of accelerated telomere attrition for fitness are still unclear. Here, we examine the relationship between telomere length (TL) and survival in a bird common to urban and rural environments, and during both early and later life. The results reveal that TL is a strong predictor of post-fledging survival and recruitment in both habitats but, crucially, selective disappearance of individuals with short telomeres early in life is more pronounced in the urban environment, resulting in a longer average TL among the adult population. However, following recruitment, we found no difference in the relationship between TL and survival between the urban and rural environments. This indicates that the urban environment has negative effects in early life, while during later life the benefits could potentially outweigh the costs.

Fatty acid profiles of great tit (Parus major) eggs differ between urban and rural habitats, but not between coniferous and deciduous forests.

Early-life nutrition is an important determinant of both short- and long-term performance and fitness. The avian embryo develops within an enclosed package of nutrients, of which fatty acids (FA) are essential for many aspects of development. The FA composition of yolk depends on maternal nutrition and condition prior to egg formation, which may be affected by the external environment. To test if maternal environment affects yolk FA composition, we investigated whether the FA composition of great tit (Parus major) egg yolks differed between urban and rural habitats, and between deciduous and coniferous habitats. The results reveal differences in FA composition between eggs laid in urban and rural habitats, but not between eggs from the coniferous and deciduous habitats. To a large extent, this difference likely reflects dietary differences associated with urban habitats rather than dominating vegetation type. Specifically, urban yolks contained lower proportions of both ω-3 and ω-6 polyunsaturated FAs (PUFA), which are important for chick development. We also found a positive association between the proportion of saturated fatty acids and laying date, and a negative association between the proportion of ω-6 PUFA and clutch size. Given that urbanization is expanding rapidly, future studies should investigate whether factors such as anthropogenic food in the urban environment underlie these differences and whether they impair chick development.

Variation in early-life telomere dynamics in a long-lived bird: links to environmental conditions and survival.

Conditions experienced during early life can have profound consequences for both short- and long-term fitness. Variation in the natal environment has been shown to influence survival and reproductive performance of entire cohorts in wild vertebrate populations. Telomere dynamics potentially provide a link between the early environment and long-term fitness outcomes, yet we know little about how the environment can influence telomere dynamics in early life. We found that environmental conditions during growth have an important influence on early-life telomere length (TL) and attrition in nestlings of a long-lived bird, the European storm petrel Hydrobates pelagicus. Nestlings reared under unfavourable environmental conditions experienced significantly greater telomere loss during postnatal development compared with nestlings reared under more favourable natal conditions, which displayed a negligible change in TL. There was, however, no significant difference in pre-fledging TL between cohorts. The results suggest that early-life telomere dynamics could contribute to the marked differences in life-history traits that can arise among cohorts reared under different environmental conditions. Early-life TL was also found to be a significant predictor of survival during the nestling phase, providing further evidence for a link between variation in TL and individual fitness. To what extent the relationship between early-life TL and mortality during the nestling phase is a consequence of genetic, parental and environmental factors is currently unknown, but it is an interesting area for future research. Accelerated telomere attrition under unfavourable conditions, as observed in this study, might play a role in mediating the effects of the early-life environment on later-life performance.

Out of sight but not out of harm's way: Human disturbance reduces reproductive success of a cavity-nesting seabird.

While negative effects of human disturbance on animals living above the ground have been widely reported, few studies have considered effects on animals occupying cavities or burrows underground. It is generally assumed that, in the absence of direct visual contact, such species are less vulnerable to disturbance. Seabird colonies can support large populations of burrow- and cavity-nesting species and attract increasing numbers of tourists. We investigated the potential effects of recreational disturbance on the reproductive behaviour of the European storm petrel Hydrobates pelagicus, a nocturnally-active cavity-nesting seabird. Reproductive phenology and outcome of nests subject to high and low levels of visitor pressure were recorded in two consecutive years. Hatching success did not differ between disturbance levels, but overall nestling mortality was significantly higher in areas exposed to high visitor pressure. Although visitor numbers were consistent throughout the season, the magnitude and rate of a seasonal decline in productivity were significantly greater in nests subject to high disturbance. This study presents good evidence that, even when humans do not pose a direct mortality risk, animals may perceive them as a predation risk. This has implications for the conservation and management of a diverse range of burrow- and cavity-dwelling animals. Despite this reduction in individual fitness, overall colony productivity was reduced by ⩽1.6% compared with that expected in the absence of visitors. While the colony-level consequences at the site in question may be considered minor, conservation managers must evaluate the trade-off between potential costs and benefits of public access on a site- and species-specific basis.

Urbanisation-associated shifts in the avian metabolome within the annual cycle.

While organisms have evolved to cope with predictable changes in the environment, the rapid rate of current global change presents numerous novel and unpredictable stressors to which organisms have had less time to adapt. To persist in the urban environment, organisms must modify their physiology, morphology and behaviour accordingly. Metabolomics offers great potential for characterising organismal responses to natural and anthropogenic stressors at the systems level and can be applied to any species, even without genomic knowledge. Using metabolomic profiling of blood, we investigated how two closely related species of passerine bird respond to the urban environment. Great tits Parus major and blue tits Cyanistes caeruleus residing in urban and forest habitats were sampled during the breeding (spring) and non-breeding (winter) seasons across replicated sites in southern Sweden. During breeding, differences in the plasma metabolome between urban and forest birds were characterised by higher levels of amino acids in urban-dwelling tits and higher levels of fatty acyls in forest-dwelling tits. The suggested higher rates of fatty acid oxidation in forest tits could be driven by habitat-associated differences in diet and could explain the higher reproductive investment and success of forest tits. High levels of amino acids in breeding urban tits could reflect the lack of lipid-rich caterpillars in the urban environment and a dietary switch to protein-rich spiders, which could be of benefit for tackling inflammation and oxidative stress associated with pollution. In winter, metabolomic profiles indicated lower overall levels of amino acids and fatty acyls in urban tits, which could reflect relaxed energetic demands in the urban environment. Our metabolomic profiling of two urban-adapted species suggests that their metabolism is modified by urban living, though whether these changes represent adaptative or non-adaptive mechanisms to cope with anthropogenic challenges remains to be determined.

A systematic review of interventions targeting physical activity and/or healthy eating behaviours in adolescents: practice and training.

Despite the many health benefits of physical activity (PA) and healthy eating (HE) most adolescents do not meet current guidelines which poses future health risks. This review aimed to (1) identify whether adolescent PA and HE interventions show promise at promoting behaviour change and maintenance, (2) identify which behaviour change techniques (BCTs) are associated with promising interventions, and (3) explore the optimal approaches to training deliverers of adolescent PA/HE interventions. Nine databases were searched for randomised controlled, or quasi-experimental, trials targeting 10-19 year olds, with a primary aim to increase PA/HE, measured at baseline and at least six months post-intervention, in addition to papers reporting training of deliverers of adolescent PA/HE interventions. Included were seven PA studies, three HE studies and four studies targeting both, with two training papers. For PA studies, two were promising post-intervention with two promising BCTs, and five were promising for maintenance with two promising BCTs. For HE studies, three were promising at post-intervention and four at maintenance, both with four promising BCTs. There is preliminary evidence that interventions support adolescents to improve their PA and HE behaviours over a period of at least six months.

Pleiotropic effects of melanin pigmentation: haemoparasite infection intensity but not telomere length is associated with plumage morph in black sparrowhawks.

There is increasing recognition of the potential pleiotropic effects of melanin pigmentation, particularly on immunity, with reports of variation in haemoparasite infection intensity and immune responses between the morphs of colour-polymorphic bird species. In a population of the black sparrowhawk (Accipiter melanoleucus) in western South Africa, light morphs have a higher haemoparasite infection intensity, but no physiological effects of this are apparent. Here, we investigate the possible effects of haemoparasite infection on telomere length in this species and explore whether relative telomere length is associated with either plumage morph or sex. Using quantitative polymerase chain reaction analysis, we confirmed that dark morphs had a lower haemoparasite infection intensity than light morphs. However, we found no differences in telomere length associated with either the haemoparasite infection status or morph in adults, although males have longer telomeres than females. While differences in haemoparasite intensity between morphs are consistent with pleiotropic effects of melanin pigmentation in the black sparrowhawk, we found no evidence that telomere length was associated with haemoparasite infection. Further work is needed to investigate the implications of possible pleiotropic effects of plumage morph and their potential role in the maintenance of colour polymorphism in this species.

Reviewing essential public health functions in the Eastern Mediterranean Region post COVID-19 pandemic: a foundation for system resilience.

The COVID-19 pandemic exposed vulnerabilities in many health systems worldwide with profound implications for health and society. The public health challenges experienced during the pandemic have highlighted the importance of resilient health systems, that can adapt and transform to meet the population's evolving health needs. Essential public health functions (EPHFs) offer a holistic, integrated and sustainable approach to public health by contributing to achieving several health priorities and goals. In recent years, there has been a focused effort to conceptualise and define the EPHFs. In this paper, we describe the collaborative approach undertaken by the WHO Eastern Mediterranean Region (EMR) and UK Health Security Agency and present the findings and results of the revised EPHFs, in view of lessons learnt from the COVID-19 pandemic and the current priorities for countries across the EMR. This included conducting a desktop review, a gap and bottleneck analysis and stakeholder consultation to arrive at the revised EPHF model including four enablers and nine core functions, including a new function: public health services. The EPHFs will offer countries a complementary and synergistic approach to strengthen health systems and public health capacities and contribute to the region's ability to effectively respond to future health challenges and emergencies. By focusing on the EPHFs, countries can work towards ensuring health security as an integral goal for the health system besides universal health coverage, thus strengthening and building more resilient and equitable health systems.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.