Precision medicine seeks to use genomic data to help provide the right treatment to the right patient at the right time. Next-generation sequencing technology allows for the rapid and accurate sequencing of many genes at once. This technology is becoming more common in oncology, though the clinical benefit of incorporating it into precision medicine strategies remains under significant debate. In this manuscript, we discuss the early findings of the impact of next-generation sequencing on cancer patient outcomes. We investigate why not all patients with genomic variants linked to a specific therapy receive that therapy and describe current barriers. Finally, we explore the current state of health insurance coverage for individual genome sequencing and targeted therapies for cancer. Based on our analysis, we recommend increased transparency around the determination of “actionable mutations” and a heightened focus on investigating the variations in health insurance coverage across patients receiving sequencing-matched therapies. The speed, accuracy, and increasing affordability of next-generation sequencing (NGS) has helped spur the advent of precision medicine, which involves designing treatment based on a person’s disease-driving molecular alterations ,2,3. WhiSeveral studies have shown the utility of NGS in identifying clinically actionable mutations in cancer patients. For example, the Genomics Evidence Neoplasia Information Exchange (GENIE), an international data-sharing consortium, estimated an actionability rate of 30% across several cancers . That isUsing sequencing results to match patients to a therapy based on their cancer’s genome has shown benefits in patient outcomes  Molecular Analysis for Therapy Choice (MATCH) study , which reported in their interim analysis in May of 2016 that, of 56 enrolled patients with a mutation that matched one of the ten available treatment arms, only 33 met the eligibility criteria . By JulyOther patients are unable to access care options because of the high cost of NGS and sequencing-matched therapies. Patients looking for tumor sequencing to help match them to a therapy outside of a research study, which often covers the cost of NGS, may struggle to get insurance to cover it. Many insurance companies cover companion diagnostic DNA tests, tests of specific genes that indicate whether treatment with a specific therapy is appropriate . ReimburTo get access to sequencing-matched therapies, patients often enroll in clinical trials. Outside of clinical trials, a patient can receive a targeted therapy as long as the drug has been approved by the FDA. Receiving these therapies outside of their original indication, such as at a different dose or frequency or in patients with a different cancer type or age range, is called off-label use. Such off–label drug use is very common in routine cancer treatment, with a recent review reporting that as many as 71% of adult cancer patients receive at least one off-label cancer therapy ,34. IndeThere has been a recent call for insurance to cover NGS-based tests so that researchers and physicians can amass enough information to identify all clinically significant genetic variations to guide treatment selection for both current and future patients . One sucThe original draft of the national coverage determination (NCD) released with the F1CDx approval in November sought to outline all cases where an NGS test would be covered and propose non-coverage for any tests that failed to meet those requirements. The draft NCD proposed coverage for FDA-approved companion diagnostics and coverage with evidence development for FDA-approved non-companion diagnostics as well as non-FDA approved tests used as part of an NCI clinical trial. For tests covered with evidence development, the outcomes of sequenced patients had to be recorded in a prospective registry. The final NCD published in March 2018, however, eliminated the evidence development category and instead only provides national coverage for NGS tests with FDA approval or clearance as a companion diagnostic. All tests outside of this scope (tests that are either not FDA-approved or are not companion diagnostics) are left to the discretion of Medicare Administrative Contractors, which are private health care insurers with geographic jurisdiction to process Medicare claims.With the continued growth of NGS technology in oncology, two major questions loom large over the field. First, can the widely reported high percentage of actionable mutations in cancer cohorts translate into better patient outcomes? Second, should insurers cover the cost of genomic sequencing and sequencing-matched therapies, particularly in off-label settings?To address the first question, we propose that studies reporting the percentage of actionable mutations should use transparent, precise, and commonly accepted definitions. Additionally, studies should stratify their results to give a clear indication of the existing evidence that the mutation will lead to an improvement in a patient’s care. Finally, more studies need to examine why so few patients with actionable mutations are receiving targeted therapy. For example, studies should evaluate the timing of sequencing in a patient’s care, the ability of physicians to interpret the results, and the accessibility and affordability of off-label treatment in clinical trials or otherwise.These potential studies will also help answer the second question by uncovering the effect of insurance on patients’ utilization of and access to targeted therapies. Existing studies such as the Targeted Agent and Profiling Utilization Registry (TAPUR) Study and the NCI MATCH Study are both good examples of projects aiming to evaluate sequencing-driven cancer care ,39. ThesPIK3CA gene treated with taselisib, patients with overexpression of the protein HER2 treated with ado-trastuzumab emtansine, and patients with mutations in the FGFR pathways treated with the drug AZD4547. While these studies may uncover subpopulations where these drugs will be more effective, the overall numbers are underwhelming at present.Several stakeholders critical of CMS’s decision to cover F1CDx have emphasized the need for more evidence from trials like TAPUR and NCI MATCH to demonstrate the benefit of NGS tests beyond the current standard of testing specific actionable genes . They arThe willingness of insurers to cover sequencing-matched therapy is affected not only by outcomes, but also by cost. In the ongoing debate over health care, law makers should note the high cost of sequencing-matched therapies and establish policies for making these therapies and prescription drugs in general more affordable. One particular area of focus should be the oversight and regulation in pricing of drugs and efforts to increase price transparency, particularly for sequencing-matched therapies, which tend to be costly.Without large, multi-institutional studies evaluating outcomes for patients getting off-label therapies, insurers are left to strike a balance between covering the latest treatments and preventing overly-optimistic and potentially harmful last-ditch treatment attempts. Leaving these policy decisions in the hands of insurers instead of medical associations and federal, state, and local regulatory agencies leads to highly variable care with some patients getting coverage for the exact same care that others do not.We reported above on the promise of incorporating NGS into oncology care, while also highlighting the current shortcomings of putting this theory into practice. It is our hope that in doing so, research and attention will be directed appropriately to help maximize the benefit of precision medicine for cancer patients.


Evidence that fetal nutrition influences adult health has heightened interest in nutritional interventions targeting pregnancy. However, as is true for other placental mammals, human females have evolved mechanisms that help buffer the fetus against short-term fluctuations in maternal diet and energy status. In this review, we first discuss the evolution of increasingly elaborate vertebrate strategies of buffering offspring from environmental fluctuations during development, including the important innovation of the eutherian placenta. We then present the Maternal Nutritional Buffering Model, which argues that, in contrast to many micronutrients that must be derived from dietary sources, the effects of short-term changes in maternal macronutrient intake during pregnancy, whether due to a deficit or supplementation, will be minimized by internal buffering mechanisms that work to ensure a stable supply of essential resources. In contrast to the minimal effects of brief macronutrient supplementation, there is growing evidence that sustained improvements in early life and adult pre-pregnancy nutrition could improve birth outcomes in offspring. Building on these and other observations, we propose that strategies to improve fetal macronutrient delivery will be most effective if they modify the pregnancy metabolism of mothers by targeting nutrition prior to conception and even during early development, as a complement to the conventional focus on bolstering macronutrient intake during pregnancy itself. Our model leads to the prediction that birth weight will be more strongly influenced by the mother’s chronic pre-pregnancy nutrition than by pregnancy diet, and highlights the need for policy solutions aimed at optimizing future, intergenerational health outcomes.Lay summary: We propose that strategies to improve fetal macronutrient delivery will be most effective if they modify the pregnancy metabolism of mothers by targeting nutrition prior to conception and even during early development, as a complement to the conventional focus on bolstering macronutrient intake during pregnancy itself. Work in the past three decades has highlighted the importance of prenatal nutrition as an influence on developmental and adult biology in offspring , 2. The Although developmental and epigenetic sensitivity persists across the life span, many systems have periods of heightened sensitivity during which exposures have especially robust and long-lasting effects. For mammals in particular, many of these ‘sensitive’ or ‘critical’ periods overlap with stages of direct resource transfer between mother and offspring across the placenta or through breast milk . The modenrichment of a mother’s otherwise marginal nutrition, during early development, pregnancy or both, improves the intrauterine environment sufficient to yield long-term improvements in offspring health and human capital [From a public health and policy perspective, these findings have led to hopes that the burden of disease in future generations may be reduced by improving the health and nutritional status of pregnant women . However capital , 11.A long-standing research tradition has, however, evaluated nutritional impacts on birth outcomes , 13, whiHere we develop the Maternal Nutritional Buffering Model, an evolutionary and physiological framework for stimulating new approaches to public health interventions aimed at improving fetal nutrition and downstream health outcomes also see . We situConsider supplementing the diet of a pregnant woman. In the simplest, hypothetical scenario, the resources consumed are directly transferred to the fetus, and thus, the intervention has maximal efficacy. In this type of direct connection between maternal exposure and fetal experience, fetal access to resources is entirely dependent on the mother’s current intake. In fact, such examples are relatively rare, and serendipity of this sort is particularly unlikely for resources required in large and constant quantities, such as macronutrients. As we review below, vertebrate evolution has been marked by increasingly elaborate maternal buffering strategies aimed at maintaining stability in the offspring’s rearing environment despite environmental fluctuations in factors such as temperature and nutrient availability.Modern day fish are descendants of the earliest vertebrates, which evolved only limited capacities for parental buffering of offspring . In earlApproximately 330 million years ago (mya), the lineage leading to modern amphibians diverged from their last common ancestor with modern fish. Some amphibians derived elaborate maternal investment strategies beyond egg laying. For instance, in some species of Caecilians (one of three forms of currently living amphibians), offspring eat the parents' nutrient-rich skin, which is rapidly regenerated . HoweverBetween 330 and 310 mya the earliest amniotes evolved. These terrestrial species evolved more durable membrane-covered shells capable of surviving outside water. This group eventually gave rise to reptiles and birds in one lineage and mammals in a separate lineage. In all these species fertilization is internal, resulting in a more stable thermal, nutrient and hormonal environment during early embryonic growth. All birds and the majority of reptiles lay fertilized eggs, while non-monotreme mammals and some reptiles independently evolved the capacity for live birth. The precise temporal origin of placental mammals is unresolved, but has been placed within a broad range of ∼65 to 100 mya . These eIn placental mammals, the fetal compartment is embedded within the mother’s homeostatically regulated supply of circulating nutrients. Within this context, placentas are the interface between maternal and fetal biology, and they serve multiple roles: they facilitate the transport of essential resources like nutrients and gasses, they remove waste products generated through the fetoplacental unit’s metabolic activities, and they also help shield the fetus from exposure to potentially harmful compounds. Among placental mammals there is extensive variation in the gross morphological type of the placenta . Most prNearly all of the maternal and fetal exchange takes place in the syncytiotrophoblast lining of the placental villi, as do the majority of placental endocrine and metabolic functions . In addiSimple diffusion of a molecule across the placenta can occur in both directions (i.e. towards the mother or towards the fetus), but the direction is dependent on a concentration or electrical gradient as well as structural factors such as the thickness of the vasculosyncytial membrane separating fetal and maternal circulations in human placentas , 36. FatActive transport enhances the transfer of water-soluble molecules across lipid-rich membranes, and can move substrate against the maternal–fetal gradient. This is important when the goal is to have a consistently high substrate concentration in fetal circulation, such as with some amino acids, which are crucial building blocks used in the synthesis of proteins and peptide growth hormones . Maternade novo synthesis (macronutrients)—that link maternal diet and metabolism with the intrauterine environment experienced by offspring  and those homeostatically regulated via stores and ffspring .essential because they are not produced within the body and thus must be consumed preformed from dietary sources. Many micronutrients serve as co-factors in metabolic or enzymatic processes, and infants born with micronutrient deficiencies are at increased risk for adverse outcomes like low BW, neural tube defects and preterm delivery [Maternal biology is the sole source of nutrients and vitamins required for healthy fetal development. Some nutrients required in small quantities, in particular micronutrients such as vitamins and minerals, are classified as delivery . Some midelivery .The body has some capacity to store most essential nutrients to help ensure that needs are met should intake fall below demand . When enVitamins are essential in that they must come preformed from the diet. Vitamin D is an exception in that it can be produced in variable amounts by the body in response to sun exposure, though vitamin D deficiency is common worldwide and dietary supplementation is recommended during pregnancy , 46. VitGiven the importance of micronutrients for fetal development and the small size of maternal stores compared to reproductive needs, it is not surprising that maternal micronutrient supplementations during pregnancy often substantively improve maternal and child health outcomes , 49, altPregnancy induces changes in maternal metabolism that increase the efficiency with which some essential nutrients are extracted from the diet and utilized, which can further augment the effectiveness of interventions . For exaIn summary, pregnancy often requires an increase in dietary consumption of micronutrients relative to the non-pregnant state , 60. TheThe quantitatively most important resources required of offspring development are macronutrients: proteins, carbohydrates and fats. These provide the energy necessary for maintaining cellular function throughout the body and are the building blocks for gene products and structures like cellular membranes. Of the macronutrients, glucose is the primary energy substrate delivered between mother and fetus and is closely associated with BW variation. Clinical work has shown that maternal glucose levels directly determine fetal glucose supply , 62. As Given the pivotal role of circulating glucose to fetal growth rate, what determines maternal glucose level? Because energy substrates like glucose are required in large quantities to maintain constant functioning of every cell in the body, and since bodily requirements fluctuate across hours, weeks or even months, their availability is not relegated to chance . A motheAlthough amino acids can be used as energy substrates they are also necessary for protein synthesis and accretion within the fetus , and matFFAs are also delivered to offspring during gestation, either directly or as triglycerides (TG), which the placenta converts to FFA. They are used as energy sources, are essential to structures like cellular membranes, and late in gestation, are deposited in the human newborn’s unusually large store of body fat , 70. Matde novo and are required in large quantities late in gestation, may be mobilized from maternal or fetal fat stores if dietary intake lags behind requirements [Some FFAs have important structural or metabolic functions beyond serving as energy substrate. Although required in smaller quantities, some long-chain polyunsaturated fatty acids (LCPUFA) play an important role in fetal development, such as the well-known requirement of docosahexaenoic acid (DHA) for brain growth . LCPUFAsirements .During pregnancy, maternal metabolism is adjusted to prioritize glucose delivery to the fetus, which the fetoplacental unit itself helps orchestrate. The human placenta, with close comingling of fetal and maternal circulations, secretes more than 100 peptide and steroid hormones directly into the mother’s circulation, some of which alter maternal metabolism . This inTo summarize, in contrast to the factors transported via Pathway type A above, macronutrients important for fetal growth are delivered to maternal peripheral tissues as a normal part of homeostatic metabolic regulation, and there are multiple pathways and backup sources for meeting supply-demand imbalances . The fetAbove, we note that modifying maternal exposure to essential micronutrients (Pathway A) can lead to relatively rapid and direct changes in fetal exposure, pointing to the utility of targeted nutritional interventions during pregnancy itself. In contrast, maternal delivery of the quantitatively more important macronutrients like glucose, fatty acids or amino acids—the primary determinants of fetal growth and metabolic programming—are not passive outcomes of what the mother eats that day but are homeostatically maintained within narrow limits by maternal metabolism and more locally by the placenta (Pathway B). Because maternal metabolism has multiple sources to meet substrate needs, the fetus is largely buffered against temporary shortfalls in maternal macronutrient intake. This buffering, however, appears to work both ways: the tendency of maternal metabolism to maintain a constant internal state also tempers the beneficial impact on the fetus of supplementing maternal diet during pregnancy.Of course, macronutrient supplementation does benefit maternal nutritional status, health and offspring survival, and is thus well-justified , 77. Howin utero.The discussion of Pathway B illustrates that short-term supplements in essence ‘push’ against maternal buffering systems that are designed to absorb the impact of such short-term fluctuations—whether negative or positive—and protect metabolic set points and a stable internal milieu despite them. As we will argue, several independent lines of evidence converge on a common conclusion: policies must take a long-range view and also optimize early life nutritional conditions of the present generation if we hope to improve the nutrition that their offspring will receive Although nutrition during pregnancy itself is a weak predictor of offspring BW, there are clear links between maternal pre-pregnancy and life course nutrition and offspring BW. For instance, the well-known impact of the mother’s pre-pregnancy weight on fetal nutrition and growth  illustraConsistent with these findings, the specific components of maternal size that correlate most strongly with offspring size suggest a lingering impact of early postnatal nutrition on offspring fetal growth . For insThe most widely documented evidence for intergenerational effects of nutrition and growth comes from multi-generational cohort studies that include information on BW across multiple generations [reviewed by IGF2 gene [While correlations between fetal growth rate in mother and offspring partly reflect an effect of shared genes, there is evidence for epigenetic and developmental contributions to these correlations, suggesting that early life nutrition can have lingering biological impacts on the next generation . StudiesGF2 gene , which iGF2 gene .in utero, such as a tendency to deposit more abdominal body fat, and the reduced response of muscle to insulin, which spares glucose, could provide advantages if the postnatal environment is also nutritionally stressful [for review see Given the exquisite mammalian capacity to buffer the fetus against changes in current maternal intake, how do we make sense of the fact that fetal growth is modified in response to maternal nutritional experience years or even decades in the past? One possibility is that the associations are simply driven by constraint, with nutritional deficiencies experienced by mothers adversely affecting their own development and that of their offspring . Howeverde novo via maternal metabolism (Pathway B) are relatively decoupled from current intake, and as discussed above, appear to reflect a mother's chronic, pre-pregnancy and developmental nutritional conditions [phenotypic inertia [In contrast to micronutrients delivered via Pathway A, macronutrients that are both buffered via stores and also produced nditions , 106. Ba inertia .Although the pathways linking a mother’s own early life nutrition with her offspring’s fetal nutrition and growth are not well understood, one candidate mechanism for phenotypic inertia is the pre-placental nutritional reliance of the embryo on endometrial glands, which deliver resources to the developing embryo for the first 10–12 weeks of gestation, until the maternal circulatory supply to the placenta is more fully established . Prior tRegardless of the specific mechanisms involved, the concept of phenotypic inertia informs the Maternal Nutritional Buffering Model by implying that homeostatic systems that buffer fetal nutrition do so in part because natural selection has likely shaped maternal and placental physiology to provide integrative, and thus more reliable, information to guide offspring development. This suggests an additional reason why maternal biology might buffer the fetus against not only nutritional stress but also nutrition that is better than average: because an unusual improvement in nutrition is likely transient, it would be unwise to plan future expenditure to expect continued abundance. So long as there survival or other fitness costs associated with over-reaching one’s nutritional supply, the organism should ignore temporary, short-lived increases in maternal intake when setting developmental trajectories . BecauseThe Maternal Nutritional Buffering Model points to the need to tailor interventions based on the pathway through which a factor influences fetal development. In the case of resources derived strictly from the environment and which are partially buffered by maternal stores, such as essential vitamins and nutrients, supplementing women prior to and during pregnancy is likely to have substantial effects, especially when maternal nutrient status and dietary intake are marginal. This likely explains the relative success of many pregnancy micronutrient supplementations, such as folic acid, iron and vitamins B12, D and A , 60, 111In contrast to the above scenario, supplementing women with macronutrients during pregnancy alone is unlikely to achieve the full potential benefits associated with improving fetal nutrition because maternal metabolism has evolved mechanisms to buffer offspring from transient fluctuations in macronutrient intake. The evolutionary and physiologic background that we review helps explain the relatively modest effects of pregnancy macronutrient supplementation on birth outcomes , 76. Becatole) during one pregnancy had infants that were 124 g heavier than a control group, while women who were supplemented across one pregnancy and the lactation period of a preceding pregnancy had infants that were 150 g heavier. Women who were supplemented across two pregnancies and the intervening lactation period gave birth to infants that were 301 g heavier [atole as children gave birth to offspring who were 116 g heavier than mothers provided with the less nutritious supplement [Although available studies are few, there is evidence that sustained improvements in maternal nutrition can result in relatively large changes in offspring BW. For example, undernourished Guatemalan women who were provided a high quality protein–calorie supplement ( heavier . In a fopplement . These fpplement .The historical and intergenerational nature of prenatal nutrition underscores the need to promote policies focused on achieving long-range public health goals. Given the importance of nutrition for both maternal and offspring health, political will and financial commitments will be required to ensure adequate access to nutrition not only during pregnancy but also across the life course of multiple generations to improve population health . AlthougOur coverage in this review has by necessity been relatively selective, and we solely focused on maternal contributions to fetal nutrition and growth. Similar principles likely apply to infant metabolic programming via maternal nutrients and hormones in breast milk. Similar to fetal nutrition, breast milk composition responds directly to maternal intake of essential nutrients , but is In sum, the Maternal Nutritional Buffering Model recognizes the evolution of distinct pathways linking different types of nutritional resources to the intrauterine environment experienced by the fetus. While essential micronutrients derived from the diet and from limited maternal reserves are good candidates for interventions during pregnancy, optimal improvements in delivery of homeostatically regulated resources, such as most macronutrients, may require long-term approaches that modify the mother’s own development and metabolism to emulate longer timescales of ecological change.


Capreolus capreolus) under long-time anesthesia and free-ranging Asiatic wild asses  were LCC was used to assess stress levels in animals captured for a reintroduction project.Wildlife management, conservation interventions and wildlife research programs often involve capture, manipulation and transport of wild animals. Widespread empirical evidence across various vertebrate taxa shows that handling wildlife generally induces a severe stress response resulting in increased stress levels. The inability of individuals to appropriately respond to rapidly changing environmental conditions during and after manipulations may have deleterious and long-lasting implications on animal welfare. Therefore, mitigating stress responses in the frame of conservation interventions is a key animal welfare factor. However, we have a poor understanding of the metrics to adequately assess and monitor the dynamic physiological changes that animals undergo when subjected to stressful procedures in wild or captive conditions. A growing number of studies provide good evidence for reciprocal interactions between immune processes and stress. Here, we review the existing literature on a relatively new technique—Leukocyte Coping Capacity (LCC), a proxy for stress quantifying oxygen radical production by leukocytes. We discuss the strength and weaknesses of this immunological approach to evaluate stress, the individual capacity to cope with stress and the resulting potential implications for animal welfare. Additionally we present new data on LCC in captive roe deer ( With increasing human impact on natural ecosystems, the need for “hands-on” wildlife conservation and management is on the rise e.g., –3]. Cons. Cons3)]The broad definition of “Animal welfare” involves the well-being of animals based on the underlying psychological and physiological ability of the individual to cope with changes in its immediate environment –13. DiffThe term “stress” is a notoriously ambiguous concept in biology and medicine. After the earlier definitions of the term by Cannon  and SelyBeyond the mere definition of stress, which due to the complexity and multi-dimensionality of the phenomenon may be hard to frame, the main physiological systems for coping with stressors are relatively well-studied. There are two major mediators orchestrating the stress response in vertebrates: (i) catecholamine's controlled by the sympathetic nervous system (SNS) and (ii) glucocorticoid stress hormones  modulatIn general shorter-term/acute stress responses are thought to have an adaptive fitness value, whereas longer-term/chronic exposure to stress are generally associated with persistent immune modulation and an increase in susceptibility to diseases , 29, 32.Stress responses vary vastly among species as well as within individuals of the same species , 38–40, Several studies provide solid evidence for the strong and reciprocal interaction between immune processes and stress –54. It iPolymorphonuclear leukocytes (PMNLs), i.e., primarily neutrophil granulocytes in mammals  and heteIn wildlife the initial stress-induced oxidative burst of PMNLs acts as immediate protection against invading pathogens in the case of injury by a predator , 70. HowMcLaren et al.  developeDespite the sensitivity of PMNLs to an array of constituent mediators of the stress response, the physiological relevance of the method is promising for the following reasons: (i) PMNLs remain in their natural environment, i.e., in whole blood, allowing dynamic, and three dimensional interactions with other surrounding blood cells  as well as cell–cell interactions within and among different leukocyte cohorts, (ii) the method does not necessitate centrifugation known to change cell reactivity and also avoids “plating out” cells on glass slides as in other approaches to determine PMNL activation [Nitro blue tetrazolium test—Montes et al. ], minimiThe method provides several additional technical advantages: (i) a relatively small amount of blood  is needed to perform the assay, making it applicable for small vertebrate species, e.g., rodents, passerine bird or bat species; (ii) the procedure is rather simple, minimizing sources for error, and (iii) the response can be measured via a portable Chemiluminometer  providing immediate results, which is a great advantage in field studies in free-living animals.Measuring stress with the LCC protocol is still relatively novel. There are several aspects which require further experimental testing to establish the diagnostic efficacy of the methodology. It should be noted that studies investigating the relationship of LCC to more commonly used proxies for stress  did not find correlative relationships , 83, 84.Capture and handling of wildlife species often involve anesthesia of individuals with varying protocols which are constantly adapted for animal safety and welfare reasons , 94. AneSalmo salar) revealed that fish subjected to a 2 h period of confinement stress had a reduction in oxygen free radical production in isolated PMNLs and therefore a lower oxidative burst capacity and a debilitated innate immune response (Meles meles). The study showed that transported individuals  exhibited a detectable reduction in LCC levels when compared to individuals sampled directly at the capture site. These data indicate that transport is likely to be a compounding stressor beyond the capture event (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus) indicates that handling per se is likely to alter LCC responses. Handled animals (only for 20 s) showed remarkable reduction in LCC in comparison to non-handled animals (Capreolus capreolus) LCC levels were negatively impacted by the time of human presence at the capture site prior to the actual handling procedure, suggesting that human presence at the trapping site prior to handling should be minimized (Ursus arctos) and to evaluate whether variation in LCC co-varied with other proxies of metabolic and physiological stress, such as heart rate, N:L—ratio, blood glucose and circulating cortisol concentrations (Bos Taurus), a ring castration and a sham castration control group, suggests LCC as an innovative tool for stress and pain assessment  via LCC measurements. The authors found a larger decrease in LCC levels between week 1 and 2 for individuals that were radio-collared while this was not the case in non-collared individuals, suggesting that radio-collaring could be an additional stressor, at least in this species. In this experiment one group of individuals were housed in outdoor enclosures and the other group in indoor laboratory cages. LCC values of both groups decreased constantly over the 6-week study period, but interestingly, animals housed indoors and individually in laboratory cages showed lower LCC values despite the fact that they usually do not live in large groups and are territorial in the wild (Macaca mulatta). Individuals were housed either in a caging system (reinforced stainless steel two-tier laboratory cages) or open-rooms. Animals in the caging system exhibited significantly lower LCC responses when compared to animals held in open rooms, indicating that cage housing is associated with diminished immune function as well as higher stress levels and therefore impaired welfare . In order to further assess the validity of LCC to identify stress eliciting factors future studies should incorporate different intensities of identified or suspected stressors in a systematic approach  and include LCC in addition to other measures of stress and welfare . Such studies would be very important in order to optimize exposure to the tested stressors, thereby increasing animal welfare and furthering our understanding of the extent to which different stressors alter LCC responses.Equus hemionus) captured in Kazakhstan during a translocation project. In brief, kulan had been driven into a capture corral, rested overnight, then anesthetized via remote darting and subsequently sampled, radio-collared, and boxed for translocation the following day (Capreolus capreolus) in which LCC peak values were shown to be a robust proxy for the entire LCC curve [With the aim of evaluating capture and handling procedures and to further expand the LCC approach to different vertebrate species, we measured LCC in 12 kulan (wing day . Two kulwing day . This fiTo expand our knowledge concerning LCC dynamics and stress during long-term anesthesia (over a 120 min period) we analyzed data from 9 anesthetized captive European roe deer males. It was our aim to test recovery from initial capture and handling-induced stress  during the subsequent anesthesia, as observed in anesthetized brown bears . We founFor full details on the two projects described here, including the LCC protocol, statistical analyses and results see There are several approaches such as shifts in hormone concentrations, blood parameters and behavior to assess stress and its implications for wildlife welfare . HoweverOur review suggests that measuring LCC has the potential, amongst others, to develop in the short-term into a helpful tool to disentangle the stressful components of capture, trapping and handling procedures in wildlife. Given the implications that animal welfare perception has on the acceptance of wildlife conservation and management interventions, information provided by new techniques, such as LCC, will allow researchers to better evaluate and communicate the impact of their work while adjusting and refining procedures and protocols accordingly.This study on the European roe deer was carried out in accordance with the recommendations of the German Ministry for Environment, Health and consumer protection and all experimental procedures were approved by the ethical committee of the German Ministry for Environment, Health and consumer protection (AZ: 2347-4-2015). The Kulan project  was approved by the Committee of Forestry and Wildlife (CFW) of the Ministry of Agriculture of Kazakhstan, Document Number: KZ41VCY00098965.NH and JP initiated the LCC study on long-term anesthetized European roe deer and designed as well as conducted the experiment together with FG. PK is the head of the Kulan reintroduction project in Kazakhstan and initiated the evaluation of capture and handling procedures in cooperation with CW and NH. NH conducted all LCC measurements. Data analysis and preparation of figures was done by SV and VM. NH wrote the manuscript with contribution of VM. CW, PK, and VM revised the manuscript. All authors participated in revisions and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


At all stages of life, the body can be considered an occupational resource that interacts with social structures in identity formation and complicates personal adaptation to life transitions. As the body declines, the economic and social standing it confers also tends to decline, leading to socially embedded fears about physical decline and marginalization. This paper applies theoretical work from embodiment theory and the life course perspective to examine how perceptions of aging and life experience with sport (or lack thereof) influence exercise participation and athletic identity. Using a narrative approach, I examine in-depth interviews I conducted with elite athletes, masters’ athletes, coaches, athletic program directors, mature adults. Some participants struggled to exercise regularly, and others are exercising more in their later years than at any other point in their lives. Three key themes emerged: 1) bodily identity is tremendously important in relation to other forms of identity when it is affected by aging, ill-health, or other physical processes; 2) physical functional mobility becomes increasingly important with age; and 3) experiences with sports and athletic identity (or lack thereof) influence engagement in exercise in later life in surprising ways. The paper challenges society’s focus on youth in sports and elite athletes, to discuss how our greater longevity means that we must place more emphasis on identifying ways to keep physically active and mobile throughout adulthood.


These mechanisms are becoming more and more established and explain why bovine IgG can have immunological effects in vivo. The inclusion of oral bovine immunoglobulins in specialized dairy products and infant nutrition may therefore be a promising approach to support immune function in vulnerable groups such as infants, children, elderly and immunocompromised patients.This review aims to provide an in depth overview of the current knowledge of the effects of bovine immunoglobulins on the human immune system. The stability and functional effects of orally ingested bovine immunoglobulins in milk products are described and potential mechanisms of action are discussed. Orally ingested bovine IgG (bovine IgG) can be recovered from feces, ranging from very low levels up to 50% of the ingested IgG that has passed through the gastrointestinal tract. In infants the recovered levels are higher than in adults most likely due to differences in stomach and intestinal conditions such as pH. This indicates that bovine IgG can be functionally active throughout the gastrointestinal tract. Indeed, a large number of studies in infants and adults have shown that bovine IgG (or colostrum as a rich source thereof) can prevent gastrointestinal tract infections, upper respiratory tract infections, and LPS-induced inflammation. These studies vary considerably in target group, design, source of bovine IgG, dosage, and endpoints measured making it hard to draw general conclusions on effectiveness of bovine immunoglobulin rich preparations. Typical sources of bovine IgG used in human studies are serum-derived IgG, colostrum, colostrum-derived IgG, or milk-derived immunoglobulins. In addition, many studies have used IgG from vaccinated cows, but studies using IgG from nonimmunized animals have also been reported to be effective. Mechanistically, bovine IgG binds to many human pathogens and allergens, can neutralize experimental infection of human cells, and limits gastrointestinal inflammation. Furthermore, bovine IgG binds to human Fc receptors which, enhances phagocytosis, killing of bacteria and antigen presentation and bovine IgG supports gastrointestinal barrier function in  The first year of life is essential for infants to develop their immune system. At the same time the child is exposed to many new and potentially immunogenic stimuli such as dietary components (food) allergens and the microbiota that colonize the gastrointestinal tract. Therefore, during this year, it is crucial to have tightly regulated immune responses to prevent inflammatory responses to these (stimuli) food antigens, allergens, and commensal bacteria.It is known that human breast milk and bovine milk contain many factors that are involved in immune development. Milk contains immunoglobulins, prebiotic oligosaccharides, extracellular vesicles , antimicrobial proteins such as lysozyme, lactoperoxidase, and lactoferrin, also immunomodulatory cytokines such as IL-10 and TGF-β. In addition, breastfeeding has been shown to provide protection against gastrointestinal and respiratory tract infections . It prevAs early as 1892, Paul Ehrlich demonstrated that mouse maternal immunoglobulins confer passive immunity to their murine offspring , 7. Immuin vivo , in particular bovine IgG, have been studied since the 1970's for their potential effects on immunity and infection in humans.in vitro systems, animal models and human studies in order to determine mechanisms of action and their applicability for human health.Bovine IgG can not only bind to a wide range of pathogenic bacteria and viruses –40, but In contrast to humans, in cow's milk IgG is the main isotype present, especially in colostrum, followed by IgA and IgM . There aIn colostrum the IgG levels are much higher, reaching up to 50–100 mg/ml in the first days after birth [reviewed in ]. These This high level of IgG in colostrum has meant that many studies have used colostrum as an IgG rich source for studies, rather than purified IgG (1). However, in colostrum—as in mature milk—many other factors are present that can have immunological effects, but compared to IgG their concentrations in colostrum are relatively low. For this reason, colostrum is often regarded as an IgG1 preparation even though additional factors are present. More recently, bovine immunoglobulins isolated from serum—that is also high in IgG and low in IgM and IgA—have been used to study their effects on chronic and severe gastrointestinal disturbances in humans .Maternal serum IgG levels in cows decrease before delivery , shown bIn order to be used as an active, prophylactic ingredient in human food products, a significant amount of bovine immunoglobulins must be able to survive passage through the stomach into the small intestine, or even throughout the entire gastrointestinal (GI) tract. This has been the subject of several studies, reviewed in detail in .E. coli (EPEC)-specific IgG or active fragments thereof are present in the stools of infants that received immunoglobulins from cows immunized against EPEC  up to 50% between different studies most likely due to differences in study methodology.Collectively, the data indicates that a significant amount of orally ingested bovine IgG immunoglobulins are present throughout the GI tract, especially so in infants as they have a higher gastric pH and lower levels of proteolysis in the GI tract. The recent insights in the role of maternal breast milk immunoglobulins and its role in microbiota development in the infant stress the importance of keeping these structures intact. This is further discussed in section Immunological effects of Oral immunoglobulins of other species.Yersinia enterocolitica, Campylobacter jejuni, Escherichia coli, Klebsiella pneumoniae, Serratia marescens, Salmonella typhimurium, Staphylococcus, Streptococcus, Cryptosporidium, Helicobacter, E.coli EHEC O157:H7, Pseudomonas, and Rotavirus , influenza virus and eumoniae . This maeumoniae .In addition to immunoglobulins specific for infectious microorganisms, Collins et al. have shown that cow's milk and colostrum can also contain immunoglobulins that are specific for aeroallergens like rye-grass pollen, house dust mite, aspergillus, and wheat allergens .Although bovine milk IgG has been investigated to a larger extent than IgA, it is assumed that the specificities are similar between the two. Furthermore, a recent report compared the specificity between bovine sIgA and human sIgA isolated from milk to pathogenic and commensal bacteria and concluded that the binding characteristics of both human and bovine sIgA from milk were similar .In summary, bovine immunoglobulins can bind to a wide range of human intestinal and respiratory bacterial—as well as viral pathogens, and can also bind to inhalation and some food allergens. Figure Studies on the effect of bovine immunoglobulins on human immune function and susceptibility to infection have been performed with a wide range of Immunoglobulin rich products which can be categorized in three groups: IgG-isolates from colostrum or milk, IgG-rich colostrum, and serum-derived IgG. These products have either been tested for prophylactic or therapeutic effects in field settings or in controlled challenge models.A number of studies have been performed in which (hyperimmune) colostrum or immunoglobulins derived thereof were used for treatment in infants and young children and are summarized in Table E. coli (EPEC) to infants (10 days−18 months old) suffering from enteropathogenic E. coli (EPEC) induced diarrhea showed stool cultures being negative for EPEC in 84% of the cases (E. coli strains that did not receive the milk immunoglobulin concentrate and resulted in negative stool cultures in only 11% (1/9) of the cases. In another, double blind, placebo controlled study, performed in Bangladesh Casswall et al. could not demonstrate a significant effect of an oral bovine immunoglobulin milk concentrate from cows hyperimmunized with enterotoxicogenic E. coli (ETEC) and EPEC strains on the duration, ORS intake, stool frequency or duration of E.coli-induced acute diarrhea  against enteropathogenic he cases . The condiarrhea . Within s et al. . Since nHelicobacter pylori and Shigella, the use of hyperimmune colostrum in treatment has been less successful compared to rotavirus and E. coli induced diarrhea. In a study performed in infants in rural Bangladesh Helicobacter pylori-infected children (4–29 months of age) treatment with purified immunoglobulins from hyperimmune colostrum failed to eradicate H. pylori infection  in Bangladesh in a double blind, placebo controlled trial  colostrum resulted in significantly reduced stool frequency  showed an increased clearance of intragastric Helicobacter pylori  or a control immunoglobulin concentrate without E. coli-specific immunoglobulins. None of the volunteers in the hyperimmune colostrum, while 9/10 in the control group developed diarrhea. Similar preventive effects of E.coli specific immunoglobulins were reported by Freedman et al.  colostrum products , 94. BotCryptosporidium, Amoeba and Campylobacter. The interest in colostrum for treating HIV infected people came from an initial report that described a positive effect of an immunoglobulin preparation derived from colostrum of non-immunized cows saccharides involved in adhesion and infection than more complex bacterial pathogens. As the prevention and treatment is done with IgG raised against different strains of rotavirus and bacteria than the ones that may be actually the cause of infection, the chance of cross protection of bovine IgG to other strains of similar pathogens is better for rotavirus than for bacteria. This could be because of the more limited numbers of relevant cell surface antigens that are needed to initiate infection with rotavirus.Respiratory tract infections can be divided into upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI). Especially URTI are very common in childhood. Likewise, otitis media, which is infection of the middle ear is highly prevalent, and has partial overlap in symptoms with URTI. Multiple cohort studies have shown that breastfed infants have a lower risk to develop respiratory infections and otitis media compared to formula fed infants , 110. DuThere is a complex relationship between early respiratory tract infection and the subsequent evolution of allergy [Summarized in ]. The prIf we consider this microbial exposure hypothesis true, there is a problem with the interpretation of epidemiological cohort studies showing an increased frequency of respiratory infections in children who subsequently develop allergic sensitization and disease. The underlying defects in immune response increasing the risks of infection may be the same that increase the likelihood of allergy. This may thus imply that the infection/allergy association is not cause and effect.However, there are certain predominantly infant viral infections that have been specifically associated with the later development of asthma. Rhino-virus (RV), the common cold virus (particularly with the RV-C) induced wheezing in infancy predicts a very high probability of later asthma . To a lein vitro and animal studies have shown effects of bovine IgG and colostrum in viral respiratory tract infections. Bovine immunoglobulins can bind to—and in vitro even neutralize—RSV, a common childhood pathogen resulting in upper respiratory tract infections in infants especially in the first year of life  bovine milk as a weaning food in the first year of life had a lower chance to get respiratory infections and otitis media compared to infants that received ultra heat-treated (UHT) milk . A hypotFive studies have shown a reduced incidence or severity of upper respiratory tract infections in children that received colostrum from non-immunized cows. Of these studies, two were double blind and the other 3 studies were prospective, open or uncontrolled. The first double blind placebo controlled study was performed in IgA-deficient children with viral upper respiratory tract infections that received a sucking tablet containing 14 mg of colostrum three times per day which lowered the infection severity score after 1 week . In anotThese studies suggest that bovine colostrum can prevent upper respiratory tract infections although the open, non-controlled prospective studies should be interpreted with care. In line with studies in children, the use of colostrum to prevent respiratory tract infections has also been studied in adults and elderly people. In adults suffering from frequent upper respiratory tract infections, supplementation with a bovine IgG and lactoferrin containing whey protein fraction (600 mg/day for 90 days) showed a reduced incidence of the common cold and cold-associated symptoms compared to the placebo group in a double blind randomized, placebo controlled study . FinallyIntervention studies aiming to reduce otitis media using bovine milk proteins such as immunoglobulins are scarce. Recently, an infant formula containing milk fat globule membrane components (proteins and phospholipids) reduced the incidence of otitis media in infants 2–6 months of age in a double blind placebo controlled study . InteresTaken together, there is an increasing number of studies that suggest a role for bovine IgG or colostrum in preventing or ameliorating viral respiratory tract infections. To what extent this protective effect against infection will also affect allergy prevalence remains to be established. However, the reduced prevalence of allergic conditions amongst farming families in many countries  has beenBovine immunoglobulins can exert their effects on several levels: via direct effects on potential pathogens, via enhancing clearance of pathogens, via influencing intestinal barrier function, and via modulating immune function. This section will discuss the mechanistic evidence available to date.Clostridium difficile to human intestinal epithelium cells (Caco-2 cells) was inhibited dose-dependently by normal bovine colostral whey , irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), non-steroid anti-inflammatory drug (NSAID)-induced gut damage and perioperative endotoxemia. IgG purified from hyperimmune colostrum could protect mice against TNBS-induced colitis . Mice reAnimal models indicate that colostrum may prevent NEC. Preterm piglets fed normal bovine colostrum had better growth and lower NEC incidence, NEC severity and intestinal cytokine production compared to piglets fed formula feeding , 148. ThTwo studies have addressed the effect of immunoglobulin-enriched non-immune colostrum on peri-operative endotoxaemia as a measure for peri-operative infections. In the first study by Bölke et al. a reduced peri-operative endotoxaemia was noted after abdominal surgery, suggesting a stabilization of gut barrier function and neutralization of endotoxins by colostrum . A seconThese findings indicate that bovine IgG  prevents bacterial transfer and leakage of LPS over intestinal epithelium, modulates the expression of epithelial tight junction proteins and inhibits intestinal inflammation. This is comparable to findings in studies on the role of IgA in breastfeeding in animal models –157, sugImmunoglobulins consist of an antigen binding domain (in the variable region of the molecule) and a constant region. This constant region is essential for inducing effector functions of immunoglobulins such as phagocytosis and clearance of pathogens, complement fixation, antigen presentation and immune regulation. These downstream effector functions of immunoglobulins are dependent on binding of the constant region to immunoglobulin Fc receptors (Fc receptors). These receptors are primarily expressed on the cell surface of immune cells. Secretory IgA (sIgA) does not have these effector functions because it is a dimer containing a secretory component, and therefore the constant part is not available for binding to receptors.Streptococcus mutans with bovine IgG induced phagocytosis and killing of the bacteria by human leucocytes 2 fragments had no effect . This waThe fact that bovine IgG can bind to human FcγRII was confirmed more recently , 166. ThLess is known on the interaction of bovine IgG with other receptors. Bovine IgG1 can also bind to a non-classical receptor for IgG, the human neonatal Fc receptor FcRn, albeit with lower affinity compared to human IgG . FcRn isIn contrast to short-lived passive immunity, adaptive immune responses occur during the lifetime of an individual as an adaptive response to specific infecting pathogens on subsequent exposures and in many cases, confer lifelong protective immunity to reinfection with the same pathogens. An adaptive immune response involves activation, selection, and clonal proliferation of T and B cells. After encountering an antigen, T cells proliferate and differentiate into antigen-specific effector cells, while B cells proliferate and differentiate into antibody-secreting cells.Adaptive immune responses are initiated by activation of CD4+ T helper cells after antigen presentation by antigen presenting cells (APC). APC take up exogenous (protein) antigens from their environment via pinocytosis or receptor-mediated endocytosis, degrade them into peptides, and present these peptides in the context of MHC class II molecules to the T-cell receptor (CD3) on antigen-specific T cells .Facilitated antigen presentation has been described for cell surface expressed Fc receptors on professional antigen presenting cells. Fc receptors can internalize bacteria and viruses as well as protein antigens that are bound by circulating serum immunoglobulins, resulting in killing of pathogenic microorganisms, and antigen presentation to initiate immune responses.Low- and intermediate affinity Fc receptors have a low affinity for monomeric immunoglobulins, but have a high affinity for immune complexes. As a result, these receptors will only bind immunoglobulins when they are in complexes together with the antigens they recognize. Indeed, for Fcγ receptors , 172, FcIn line with this a recent study shows increased CD8+ T cell activation in mice infected with RSV when they received bovine colostrum orally . TherefoExperiments in murine animal models have also found increased NKT in mice that ingested colostrum containing LPS-specific bovine IgGs . SimilarIn addition to oral bovine immunoglobulins, several studies with murine, porcine and human oral immunoglobulins have elucidated mechanisms that may also occur after ingestion of bovine immunoglobulins.A series of recent studies in mice have shown yet another potential mechanism for the presence of immunoglobulins in the intestinal lumen. These studies have shown that locally produced intestinal IgA can bind to intestinal bacteria and modify the microbiota composition as well as immune responses toward bacteria in the gut –184. TheIndeed, maternal sIgA in breast milk was shown to significantly modify microbiota composition at weaning and later in life, limit translocation of pathogens in suckling pups and ameliorated DSS induced colitis . In addiSimilar effects of IgG in breast milk of mice have been obtained in a study in which immune complexes of murine breast milk IgG and allergens prevented the development of experimentally induced asthma . IgG-allAs described above, bovine milk contains IgG directed against inhalation allergens . The funImmune complexes of maternal breast milk immunoglobulins with maternal GI microbiota components have been shown to be crucial for delivering tryptophan-derived AhR ligands that promote barrier function in the suckling pups in an IL-22 and Innate Lymphocytic Cell type 3 (ILC3)-dependent manner .Oral ingestion of porcine immunoglobulin also contributes to prevention of inflammatory tissue damage in LPS-induced acute lung inflammation in mice. Oral IgG enhanced the expression of IL-10 producing Treg, decreasing Th1 and Th2 cytokines and decreasing chemokine production in the lung in response to LPS .These studies indicate that oral immunoglobulins may help to regulate immune responses to the microbiota as well as allergens—on the one hand promoting immune exclusion of pathogens, and on the other hand preventing excessive immune responses to commensal bacteria. Studies on effects of bovine Ig and colostrum ingestion on fecal microbiota composition in infants during colonization of the GI tract have not been performed to date, but based on these findings it may be expected that oral intake of bovine IgG may similarly affect microbiota composition, allergy and immune development in humans.The protective role of IgA in breast milk is well-documented. IgA protects infants against infection, shapes the microbiota and creates a non-inflammatory response against the microbiota, thus preventing intestinal inflammation.As described above, bovine IgG has a number of similar effects: binding to human-relevant pathogens, effects on phagocytosis mediated through Fc receptors for human IgG and prevention of infection in human studies. So functionally, bovine IgG does have effects on the human immune system beyond just binding to potential pathogens. In addition, especially in young infants, IgG does seem to pass through the gastrointestinal tract without being fully degraded by digestion, thus leaving its functional aspects intact. As the fine specificity as well as the effector functions of bovine IgG are not identical to breast milk IgA (and IgG), one question that remains to be answered in clinical studies is if inclusion of functionally active bovine immunoglobulins in infant nutrition can fully restore the lack of maternal IgA in bottle fed children.Immune support by bovine immunoglobulins as an alternative for breast milk-derived IgA is especially relevant in the period just after birth in case the mother cannot breastfeed her child and is dependent on bottle feeding, but also in the weaning period at around 4–6 months when respiratory and gastrointestinal infections are known to increase as the passively acquired maternal IgG in serum, as well as the maternal breast milk-derived IgA in the gastrointestinal tract of the infant, have decreased to very low levels.It should be stated though, that the increased prevalence of infections after weaning is not completely related to deprivation of IgA but is also linked to the introduction of new foods, an increased exposure to the outside world and in part by the absence of additional protective factors in breast milk.Currently, formula fed children receive no or very low levels of functionally active bovine immunoglobulins. This is because current foods processing technologies as well as legislation strongly depend on heating as the technique of choice to achieve microbiological safety. Overcoming these challenges by applying novel food processing technologies may enable the application of bovine immunoglobulins in infant nutrition.Future research will be needed to confirm if this will indeed result in a reduction in gastrointestinal and respiratory infections, and if this will also be associated with a decreased prevalence of asthma that is linked to early respiratory tract infections in infants.LU, JL, HS, JW, and RvN all contributed to the writing of the manuscript.LU and RvN are employees of FrieslandCampina. JW has been the PI for a trial of a cow milk formula with prebiotics for the prevention of allergy funded by Danone/Nutricia. JL, HS have no conflicts of interest to report. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in defective organization of the cytoskeleton in hematopoietic tissues. They share some overlapping features such as a combined immunodeficiency, eczema and a predisposition to autoimmunity and malignancy, but also have some unique features that make them relatively easy to diagnose by clinical means. Both diseases can be cured by HSCT in a large proportion of patients. In WAS it is sometimes difficult to establish an indication for HSCT due to the large variability of disease severity, while HSCT is probably indicated in all patients affected by DOCK8 deficiency. There is considerably more published HSCT experience for WAS than for DOCK8 deficiency, but many open questions remain, which will be discussed in this review. Due to the extreme variance of disease severity, determining the best treatment approach for milder affected WAS patients remains a challenge.- HSCT is the treatment of choice for DOCK8 deficiency due to the early mortality and high incidence of significant infections and malignancy.- Long term follow-up is needed to determine the risk of malignancy in DOCK8 deficiency post HSCT and the long-term outcome of vascular disease.WAS gene. The fact that the WAS protein, which is absent or defective in WAS patients, is a critical regulator of the cytoskeleton and is expressed in all hematopoietic cell lineages, helps explain the multi-faceted manifestations of the disease. These include eczema, a combined immunodeficiency, thrombocytopenia, autoimmunity and a predisposition to mostly hematopoietic malignancy (The Wiskott-Aldrich syndrome (WAS) occurs in males with hemizygous mutations in the X-chromosomal lignancy –4.A striking feature of WAS is the extreme variability of disease severity. It ranges from infants with severe immunodeficiency, catastrophic bleeding complications and a severely reduced life expectancy to patients with no symptoms except thrombocytopenia and a presumably normal life expectancy , 6. PatiIt is widely accepted that for patients with a classic WAS phenotype consisting of a clinically relevant immunodeficiency and thrombocytopenia with or without eczema, an allogeneic hematopoietic stem cell transplantation (HSCT) is absolutely indicated. This should be carried out as soon as the diagnosis is established, the best donor has been identified, and the patient's condition is optimized, which is typically not before 1 year of age. Development of autoimmune/autoinflammatory phenomena or malignancy also should be considered as a strong indication for HSCT.For patients with a milder phenotype, the decision to proceed to HSCT is a much more difficult one, as some of those can have a normal life expectancy. Nevertheless, patients with an initial mild phenotype also have a high incidence of severe disease related complications—which presumably negatively affects their quality of life . For exaWAS was one of the first diseases treated by HSCT in 1968  and sincThe seminal registry study of 170 WAS patients transplanted between 1968 and 1996 reported an overall survival (OS) of 87% with HLA-matched sibling donors (MSD), 71% with matched unrelated donors (MUD), and 52% with mismatched family donors (MMFD) . A largeSeveral recent single-center reports have published excellent survival data, but larger, multi-center analyses reporting more recent results with state-of-the-art donor selection, conditioning regimens, and supportive care are currently missing –15. ThusConservative treatment for classic WAS patients before HSCT should include bleeding prevention, antibiotic prophylaxis, immunoglobulin substitution, and eczema treatment. For those patients with a milder disease phenotype, all those conservative measures may also be indicated and can help to ameliorate disease burden. Platelet transfusions are necessary for life-threatening bleeding episodes and for surgical procedures. We discourage the routine prophylactic use of platelet transfusions in order to avoid development of anti-HLA or anti-platelet antibodies. Splenectomy is often an effective measure to elevate platelet counts and minimize the risk for bleeding, but it can increase the risk for fatal infectious complications and make a subsequent HSCT more risky . It shouWAS is also one of the first diseases in which autologous stem cell gene therapy was clinically tested. Early optimism about good efficacy lessened when very high rates of insertional mutagenesis were observed with a retroviral vector . ConsecuRecent improvements of HSCT have led to excellent cure rates in WAS with HLA-matched as well as -haploidentical donors. HSCT at an early age is the treatment of choice for all classic WAS patients. It should also be discussed for patients with a milder phenotype, keeping in mind that it remains a sometimes dangerous procedure. This stresses the need for further improvement of HSCT and development of potentially safer therapies such as gene therapy. Given the portfolio of treatment options and the extreme variance of disease severity, it will be an ongoing challenge in the future to define the best modality for each and every patient and new biomarkers to predict disease outcome are urgently needed.DOCK8 were described in 2009 to cause a combined immunodeficiency previously referred to as autosomal recessive Hyper IgE syndrome  alpha has been used with some success as adjunctive therapy to treat warts, molluscum or resistant HSV infections  is a good choice for prophylaxis as fections –43, but HSCT is considered curative for DOCK8 deficiency, and with transplant regimens and supportive care improving, HSCT should be discussed at the time of diagnosis, ideally prior to development of significant end organ damage. However, some questions over the long-term complications and prognosis remain. The vasculopathy of DOCK8 deficiency remains poorly understood, and long-term studies following HSCT are needed. The arterial aneurysm and stenosis occasionally seen are thought to be driven by inflammation or viral infection, and the hope is that HSCT will therefore at least stabilize disease. Skin microbiome studies in DOCK8 deficiency reveal a high burden of virus, largely HPV, even in areas without apparent disease . The pooMA and AF wrote the manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services. Millennium developmental goals (MDG) 4 and 5 specifically focus on reducing child mortality and improving maternal health . DespiteThe most common contributor to early neonatal mortality is birth asphyxia with prematurity, infections, and low birth weight being other major contributors. Four million newborn infants experience birth asphyxia each year, accounting for an estimated one million deaths and 42 million disability-adjusted life years [With the advent of therapeutic hypothermia (TH), improved outcomes are being reported in moderate HIE. TH, however, has not demonstrated improvement in outcomes related to severe HIE. As hypothermia, both whole body and head cooling, is being evaluated and used across the globe, several limitations for its use, related to accessibility, provision of adequate facilities for initiation and monitoring hypothermia and financial limitations—especially in developing countries—are being recognized. This has led clinicians and researchers to continue evaluating complementary and/or alternative therapies for infants with HIE. In this review, we will discuss current and emerging therapies in the management of HIE, other than hypothermia.Any pregnancy that is identified as being at high risk for neonatal complications should ideally be delivered at a tertiary care center with trained and experienced resuscitators. Management of an infant who is depressed at birth involves following accepted guidelines such as those published by ILCOR and Neonatal Resuscitation Program . The infThe primary pathophysiologic event that results in HIE is impaired oxygen delivery to the brain tissue. This could be caused by reduced oxygen carrying capacity primarily from the hypoxic component or from reduced cerebral blood flow due to volume loss or impaired circulation. Often, a combination of these events is seen. While in some infants the exact causative event cannot be identified, the pathophysiology of brain injury in HIE is well described in term and near term infants.Primary energy failure occurring from the initial hypoxic ischemic (HI) insult  is charaTimely clinical assessment is essential to facilitate intervention in the latent period. Anticipation from prenatal history and risk factors prepares the team for potential HIE. A detailed neurological exam helps the clinician determining the severity, generally classified as mild, moderate or severe HIE. TH is typically started within 6 h of birth for it to be effective, before secondary energy failure ensues. However, the concept of tertiary brain injury and alternate therapies that could continue to affect prognosis has expanded the treatment window of HIE. Despite advances in management options, it is difficult to predict HIE in infants, as some of them develop HIE in spite of a normal neurological exam. Recently, specific biomarkers of neuronal injury are being explored for earlier identification of HIE in these infants.Due to the varied clinical presentation of HIE, it is difficult to predict outcomes early during the course, when intervention with targeted therapies would have maximal effect. Hence, biomarkers that could help detect presence and severity of HIE are being evaluated. These are chemicals that are measurable in blood, urine, cerebrospinal fluid (CSF), or from multiple locations reflective of brain injury or regeneration. Currently, there are no easily available and specific biomarkers for clinical use. In this section, we will describe emerging biomarkers in HIE.S100B is a calcium binding protein released by brain glial cells in response to injury . ElevateNeuron specific enolase (NSE) is a glycolytic isoenzyme that is released after neuronal death. Celtik et al. identified NSE cut off values that could help differentiate mild moderate and severe encephalopathy . AnotherGlial fibrillary acidic protein (GFAP) is released with damage to astroglial cells and levels in blood and CSF have been seen to correlate with severity of HIE, MRI changes, and developmental outcomes in small studies ,20. HoweSeveral other biomarkers of brain injury including ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and total tau protein also hold promise as early biomarkers of brain injury in HIE that are being studied further ,21.Several cytokines are released in acute HIE and their potential as early and accurate biomarkers is being extensively researched. Interleukin (IL)-6 and IL-16 in cord blood were found to be significantly associated with electrographic and clinical HIE severity in a study of full term infants . In anotMetabolomic analyses are being used in various conditions to identify its presence in time for appropriate therapy. Distinct patterns of changes in body metabolites have been evaluated in a recent metabolomic analysis in a non-human primate model of HIE. Eight metabolites  were noted to correlate with adverse neurodevelopmental outcomes  in this Magnetic resonance spectroscopy (MRS) has significantly improved our understanding of the changes in brain metabolism and evolution of brain injury after a hypoxic ischemic insult. It could help define the severity of injury if done during the treatment window (within 6 h) by estimating phosphocreatine (PCr) and cerebral lactate or inorganic phosphate. High PCr has been associated with a favorable outcome  while hiMost of the neuroprotective strategies being evaluated for use in management of HIE , are priEither by delayed cord clamping or by the process or cord milking/stripping may impart a neuroprotective effect, besides improving hemodynamics . Full-teUse of vasopressin as an alternative to epinephrine in neonatal resuscitation is being evaluated in pre-clinical studies. This medication has a neuroprotective potential as studies in rat and guinea pig have demonstrated that vasopressin activates hippocampal interneurons, silencing synchronous neuronal activity . This maErythopoietin (Epo) is an endogenous protein, synthesized in the fetal liver that has an impact on multiple critical pathways. Besides stimulating erythropoiesis, Epo is a cytokine that influences the body’s immune response . AdditioDarbepoietin (darbe) is a long acting erythropoietin analogue that offers the additional benefit of once weekly administration. A small randomized trial evaluating the use of darbe as adjunctive therapy to hypothermia in the first 12 h of life and repeated at one week of life demonstrated a good safety profile of this medication . A largeRecent experimental studies in animal models have indicated that various mechanisms of action are involved in the process by which umbilical cord blood cells (UCBCs) protect the brain from hypoxic ischemic injury. These stem cells are predominantly derived from two sources—bone marrow derived mesenchymal stem cells (BM-MSC) and umbilical cord blood derived mesenchymal stem cells (UCB-MSC) . PreclinThe concept of remote ischemic conditioning (RIPC) involves delivery of sub-lethal small ischemic insults, remote from the area of injury, that activate endogenous repair pathways which potentially help in reducing the extent of original ischemic injury. This has previously been studied in adult cardiac injury , howeverThe endocannabinoid system has been recognized as an important neuroregulatory mechanism that could help in protection from brain injury. Activation of this system has been shown to decrease glutamate excitotoxicity and activation of microglia and cell death pathways. Use of a cannabinoid (CBD) receptor 1 and 2 (CBR1 and CBR2) agonist WIN 55212-2 in a rodent model of neonatal HIE demonstrated protective effects by prevention of glutamate release, TNF alpha accumulation, and iNOS induction, resulting in decreased cell death . AdditioMelatonin is an endogenous neuroendocrine moiety secreted by the pineal gland and well known for its role in modulating the circadian rhythm. Besides this, melatonin has several other mechanisms that suggest an important role in recovery and repair from brain injury. Melatonin plays an important role in normal glial development  and has Gangliosides are sphingolipids that serve an important function in maintaining cell membrane integrity. In a rat model of neonatal hypoxic ischemic injury, reduced ganglioside, phospholipid, and cholesterol contents in the hippocampus were noted . MonosiaAcute hypoxic ischemic insult leads to NMDA receptor activation through neuronal depolarization. Xenon inhibits NMDA signaling and thus may play a role in reducing the acute cell injury. While studies in the piglet model of birth asphyxia suggest a benefit to the combined modality of treatment with hypothermia and xenon ,71, a prThis is another significantly less expensive noble gas, that has demonstrated significant neuroprotection in animal models of HIE. In an extensive piglet model of ischemic injury, Broad et al. showed augmentation of hypothermic neuroprotection with argon use. They demonstrated reduced brain cell death, MRS, and aEEG improvements with combined argon hypothermia treatment . AdditioOxidant injury by free radicals and superoxides formed through activation of the xanthine oxidase pathway contribute to the damage caused by a hypoxic ischemic insult. Allopurinol is a xanthine oxidase inhibitor that is being investigated as a potential agent for use in treatment of HIE. Preclinical studies in various rodent  and mamm4 use in infants with severe asphyxia, without hypothermia therapy, revealed encouraging short term outcomes compared to standard supportive treatment [4 use in HIE noted inconsistent evidence of benefit as well as little consensus in dose and timing of administration [4 in HIE concluded that there was improvement in short-term outcomes without significant increase in side effects [4 is thought to be a potentially viable therapy in low resource settings, in spite of its side effects [Magnesium sulfate is an NMDA receptor antagonist believed to reduce excitotoxic damage after a hypoxic ischemic insult. It is now being widely used antenatally for neuroprotection in preterm deliveries. Initial interest in use of this medication was generated due to low magnesium levels being noted in infants with HIE . A prospreatment . A systestration . Though stration . A meta- effects . However effects . Due to  effects .Topiramate blocks the voltage-dependent sodium and calcium channels and also inhibits the excitatory glutamate pathway while enhancing the inhibitory effects of gamma-aminobutyric acid (GABA). All these effects would work favorably in the pathophysiology of HIE. In newborns, it has been extensively studied in the management of HIE in combination with hypothermia. The short-term and safety data support its use in combination with hypothermia in exploring the possible neuroprotective effects . AlthougPreclinical studies in models of ischemic stroke have revealed that azithromycin has a neuroprotective effect . Recent With the discovery of more therapeutic targets for management of HIE, there is potential for combination and adjunctive therapies with agents that may affect the pathophysiological process at different phases. Additionally, TH is being explored for mild HIE, as neurological deficits have been noted in these infants as well . MelatonChanges that occur in the brain after perinatal ischemic injury over time include loss of myelin, decreased neurogenesis, and reduced plasticity of the brain leading to tertiary brain damage . These mTrichostatin-A, a histone deacetylase (HDAC) inhibitor has been shown to abolish behavioral and neuroendocrine deficits from early life stresses by promoting demethylation and possibly inducing epigenetic modifications . HDAC inStem cell therapy offers enormous potential for stimulation of endogenous neural stem cells; to redirect new cell production from astroglia to oligodendrocytes and neurons following acute insult. Repeated treatments and delayed treatment in animal models has expanded the therapeutic window for treatment of tertiary brain damage by inducing repair and regeneration ,103. ActMost of the therapies discussed above are studied in animal models with few current clinical studies, particularly in neonates with hypoxic ischemic encephalopathy. However, current research suggesting targets for therapy in infants with HIE in the tertiary phase, months to years after the acute insult offers hope to children with this devastating disease.Therapeutic hypothermia, while standard of care in developed countries, remains an expensive and sometimes unaffordable modality of treatment in resource limited settings. Practical difficulties are often encountered in transferring patients, often in rural settings to tertiary care centers within the 6-h window for therapeutic hypothermia. An additional concern initially identified in a randomized controlled trial of TH by Robertson et al. was the high mortality rate that was noted in the enrolled infants . A systeBirth asphyxia contributes to a significantly higher burden of neonatal mortality and morbidity globally, more so in developing countries. Neonatal HIE, apart from increased mortality leads to devastating neurological consequences such as cerebral palsy, epilepsy, and mental retardation. With the advent and widespread clinical use of TH over the last decade, the prognosis of moderate HIE has significantly improved. However, TH is expensive, needs a multidisciplinary team and is further limited by narrow therapeutic window for initiation. With issues of access to health care and the burden of birth asphyxia shifting to developing and least developed nations, there is a need for alternative and supplementary neuroprotective agents. Low cost and easy availability along with ease of use would assist in ensuring that these therapies have global applicability. Several of the promising modalities we have described in this review are still in the preclinical stage. It is uncertain how many of these therapies, alone or in combination, will achieve widespread use in the management of neonatal HIE. Large well designed randomized control trials in developed countries as well as in low resource settings, are required to prove the safety and efficacy of these therapies, prior to widespread clinical use. Neonatal HIE remains a condition of global importance with significant disparities in available treatment options among developed and developing countries. Hence, a concerted effort to address this problem on a global scale is essential.


There is considerable evidence that health systems, in so far as they ensure access to healthcare, promote population health even independent of other determinants. Access to child health services remains integral to improving child health outcomes. Cognisant that improvements in child health have been unevenly distributed, it is imperative that health services and research focus on the disadvantaged groups. Children residing in urban slums are known to face a health disadvantage that is masked by the common view of an urban health advantage. Granted increasing urbanisation rates and proliferation of urban slums resulting from urban poverty, the health of under-five children in slums remains a public health imperative in Malawi. We explored determinants of healthcare-seeking from a biomedical health provider for childhood symptoms of fever, cough with fast breathing and diarrhoea in three urban slums of Lilongwe, Malawi.This was a population-based cross-sectional study involving 543 caregivers of under-five children. Data on childhood morbidity and healthcare seeking in three months period were collected using face-to-face interviews guided by a validated questionnaire. Data were entered in CS-Pro 5.0 and analysed in SPSS version 20 using descriptive statistics and logistic regression analyses.AOR = 0.54; 95% CI: 0.30–0.99); when illness was perceived to be severe ; when the presenting symptom was fever . Home management of childhood illness was negatively associated with care-seeking  and timely care-seeking . Caregivers with good knowledge of child danger signs were less likely to seek care timely .61% of caregivers sought healthcare albeit 53% of them sought healthcare late. Public health facilities constituted the most frequently used health providers. Healthcare was more likely to be sought: for younger than older under-five children (Even in the context of geographical proximity to healthcare services, caregivers in urban slums may not seek healthcare or when they do so the majority may not undertake timely healthcare care seeking. Factors related to the child, the type of illness, and the caregiver are central to the healthcare decision making dynamics. Improving access to under-five child health services therefore requires considering multiple factors. Global trends pertaining to child health show a significant decline in child morbidity and mortality over the past few decades reflecting successes of various public health efforts –3. MalawThe substantial achievements notwithstanding, child health indicators for Malawi, such as under-five mortality rate of 63 deaths per 1000 live births, neonatal and infant mortality rates of 27 and 42 deaths per 1000 live births respectively . The IntIncreased access to essential child health services therefore remains integral to efforts to achieve Sustainable Development Goals (SDG) particularly target 3.1 that asserts “End preventable deaths of new-borns and children under 5 years of age, with all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births” . In Malawi, iCCM has only been implemented in rural areas  using Health Surveillance Assistants – a cadre of lay community health workers. It may be worthwhile to consider implementing iCCM even in urban slums granted our study findings that healthcare seeking, although relatively high, is still suboptimal and that care is sought late by almost half of those that seek it. In the context of urban health, iCCM in urban slums will reduce congestion at urban health centres effectively lessening the burden of long waiting times, and potentially contributing to more time spent on examining children with severe illness at a health facility. Indeed, long waiting times and suboptimal examination of the sick child by health workers have been shown to have negative effect on preference for health facility in the event of childhood illness –53. It eWhilst we acknowledge the definition of prompt care-seeking being care sought within 24 h period as cited hitherto, based on Heads of States commitment on Roll Back Malaria, similar to Rutebemberwa et al. (2010), we used definition of ‘next day’ from onset of symptoms to approximate the 24-h period. This approach was deemed to be more practical and contextually relevant for eliciting time in our study granted low education levels and that people hardly use clocks/watches to undertake time  estimations. Our experience in this study therefore renders support to a call for more reliable methods of retrospective time estimation in surveys conducted in developing country contexts, especially among participants of low literacy.Consistent with some similar studies , 54, 55,Our study has also demonstrated that undertaking home management of childhood illness negatively influenced both care-seeking and timely care-seeking from a health facility. This may be explained by the possibility that in some cases, home management may have led to childhood symptoms subsiding, effectively eliminating the need for care-seeking from a health provider. Additionally, caregivers may have been watchfully waiting for the effect of their home remedies hence delayed in seeking care. Implementation of community IMCI in Malawi and elsewhere provides for educating caregivers on home management of some less severe cases of childhood illnesses . The facAdditionally, ensuring that home management is conducted correctly represents an important area of focus but one which was beyond the scope of our study. Evidence pertaining to appropriateness of home management undertaken for various childhood illnesses including determinants of home management in the context of IMCI remains sparse in Malawi and among caregivers in urban slums, in particular. Specific evidence in this area is therefore warranted.Unsurprisingly, illness severity influenced healthcare seeking as the odds of seeking care from a biomedical health provider were more than twice for childhood illness perceived to be more severe relative to that perceived to be of minor severity. This renders support to similar findings in studies conducted in Malawi , 57, KenIn our study, having fever predicted care-seeking but ARI symptoms and diarrhoea did not. Since, by classification, ARI symptoms are characterised by coughing and fast breathing, the expectation was that this combination would have been considered serious enough to warrant care-seeking from a health provider. Children with ARI symptoms need prompt antibiotic treatment available from a health facility, hence this finding presents a public health challenge for child health in urban slums that may be arising from lack of knowledge on the seriousness of ARI symptoms. Similar results, albeit for coughing symptoms were found in a study in the Nairobi slums in Kenya. Rationalising this finding, the authors posited that the fact that respiratory infections were so common in urban slum setting of their study, caregivers may have thought illness with respiratory infection symptoms were like any other experienced many times before hence did not bother seeking healthcare from a facility . Indeed,While distance to health facility has been shown to be a significant predictor of care-seeking, timely care-seeking and risk of child mortality in previous studies elsewhere , 60, 61,In our study, household wealth did not predict care-seeking or timely care-seeking from health facilities. It is probable that the fact that a significant majority of caregivers utilized public health facilities which provide free services at the point of use in Malawi, entailed that household wealth may not have had a significant effect in care-seeking dynamics. Relatedly, our discrete choice experiment study responded to by a subset of participants used in this study revealed that cost of healthcare negatively influenced the choice of a health facility in the event of childhood illness, effectively intimating caregivers’ aversion with cost of healthcare .Similarly, autonomy and social capital of caregivers did not significantly predict care-seeking or timely care-seeking from biomedical health providers. These results contrast with those found elsewhere that demonstrated autonomy , 64 and Knowledge of child danger signs neither determined care-seeking nor timely care-seeking in our study. This contrasts with other studies that have demonstrated that knowledge of danger signs or symptom recognition is a critical predictor of care-seeking for child health services , 66. IndSome limitations are acknowledged for our study. We relied on self-reported information hence there is potential for reporting bias. There was also potential for recall bias considering the long recall period. However, we undertook verification of reported child morbidity and care-seeking information with what is documented in the child health passports – a health booklet that keeps record of health information including symptom description, frequency and duration, at individual client level. This arguably reduced reporting and recall bias. The cross-section nature of the study limited opportunity to observe any seasonal or time variations in both disease patterns and corresponding healthcare-seeking dynamics, both of which could have contributed to a deeper understanding of the phenomenon under study. The study’s strengths relate to: a rigorous participant selection process which included an initial census to enumerate study participants; focusing on an important group of the population (i.e. residents of urban slums) which is understudied albeit increasing in size due to rapid urbanization, slow economic growth and the so-called urbanization of poverty.While our study focused on a general issue pertaining to healthcare seeking for under-five child health services, generalization of findings may be comfortably undertaken only in similar contexts of urban slums. Furthermore, some findings may need to be interpreted with caution, such as the lack of association between education of caregiver to care-seeking and timely care-seeking, given established evidence in this regard.In conclusion, the findings of this study show that healthcare seeking from a biomedical health provider among caregivers of under-five children in urban slums remains suboptimal and mostly sought untimely. Factors related to illness of the child ; the child (age of child) and geographical environment (slum residence) influence care-seeking decisions.The results of the baseline study point to various implications for policy and practice. There is need to focus on child health programming as delivered to residents in urban slums especially with regard to interface between facility based IMCI and the community component in so far as strategies to promote child healthcare seeking and the actual utilisation of health services are concerned. The concept of Community Case Management, while at present considered more appropriate for rural areas who are relatively farther away from health facilities, might as well be appropriate for caregivers in urban slums in Malawi. While symptom recognition, knowledge of danger signs and home management of common childhood illness are important programmatically, health education is imperative so that they do not hinder appropriate care-seeking.Disaggregated analysis of urban health data is essential for epidemiological mapping that should inform context specific strategies of delivering child health interventions. The extent to which child health and survival efforts are promoted in urban Malawi therefore depends on acknowledgement that residents in urban slums may not enjoy a health advantage as aggregate urban health indicators suggest. Furthermore, the cognizance that the urban context in itself is a determinant of health hence the need for an urban health agenda that responds to the differential needs of different urban population groups should warrant a deeper look in urban child health research, policy and practice.