Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic‐based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two‐way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis. The lung is reportedly made up of dozens of cell types and has evolved architecturally into a series of branching airways and alveoli to support efficient gas exchange Figure .1 The abLung fibrosis is a condition that is characterised by accumulation of extracellular matrix (ECM) within the lung. When progressive, the accumulating ECM can cause alveolar distortion and loss of gas exchange, eventually leading to respiratory insufficiency. The exact aetiology of most fibrotic lung diseases is unknown (i.e. idiopathic), although there are genetic mutations (e.g. in telomerase or surfactant protein C genes) that can lead to fibrosis and there are environmental insults (e.g. asbestos and silica) that are also known to cause development of lung fibrosis. The most common form of idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF), and this form of lung fibrosis in humans is the most well‐studied.Despite decades of study, the pathogenesis of pulmonary fibrosis is poorly understood, and there has been ongoing controversy over the role that immune mechanisms may play in disease progression. Most notably, the failure of many immunomodulatory therapies (e.g. augmentation of interferon gamma (IFNγ),Because humans with IPF are generally diagnosed with end‐stage disease, it can be a challenge to study the natural progression of lung fibrosis in humans. Therefore, a number of animal models have been developed that involve chemically induced lung injury, particulates, genetically modified mice, viral infections and radiation. In this review, we will restrict our analyses to three animal models of lung fibrosis, namely intratracheal delivery of bleomycin, silica‐induced lung fibrosis, and a model of viral‐induced pneumonitis and fibrosis following stem cell transplant to highlight the influences of innate immunity on initiation and progression of disease. While these animal models are useful for studies of disease mechanisms that we hope are shared between rodents and humans, it should be acknowledged that none of these animal models fully recapitulate the natural history, time course, histology and pathogenesis of the human diseases.A number of innate immune receptors have been implicated in the pathogenesis of lung fibrosis, and many of these receptors are expressed on both structural and immune cells. One family of receptors is known as pattern or pathogen recognition receptors (PRRs), and they sense ‘danger’ in the form of injury or infection by recognition of pathogen‐associated molecular patterns (PAMPs) or danger‐associated molecular patterns known as DAMPs. This PRR family includes Toll‐like receptors (TLRs), nucleotide‐binding oligomerisation domain receptors (NOD‐like receptors or NLRs), C‐type lectin receptors, retinoic acid‐inducible gene 1(RIG‐1)‐like receptors (RLRs) and cytosolic DNA receptors. PAMP ligands for PRRs include substances such as lipopolysaccharide (LPS), peptidoglycan and flagellin, which are components of bacterial surfaces, but also include unique pathogen genomic structures such as double‐stranded RNA and CpG‐rich DNA that is enriched in microbes. In contrast, the DAMP ligands include substances such as heat‐shock proteins−/− mice are protected from bleomycin‐induced fibrosis.The inflammasome is the name given to a multimeric collection of proteins that assemble in response to DAMPs and PAMPs to activate caspase 1 to allow cleavage of pro‐IL‐1β and pro‐IL‐18 into their biologically active forms. There are two main steps involved in activating inflammasomes. The first step is the priming step, and it is mediated by TLR activation to upregulate NF‐kB and induce transcription of inflammasome component genes and also to increase the transcription of pro‐IL‐1β. The second step is the assembly of the multiprotein complex and activation of caspase 1. Release of PAMPs and DAMPs caused by profibrotic injury or infection leads to inflammasome activation, and there are several different kinds of inflammasome scaffolds that can form. Interestingly, it has been suggested that as fibrosis progresses and the lung stiffens, the increased mechanosensing by cells in the lung may lead to ongoing inflammasome activation as a way to perpetuate lung fibrosis.2 that is caused by epigenetic alterations post‐bone marrow transplantIn terms of silica‐induced fibrosis, inflammasome activation in macrophages that take up the silica particles is well defined as a critical mediator of the pathogenesis of this disease e.g. , 25, 26.In addition to the pro‐inflammatory signalling by PAMPs and DAMPs described above, genetic studies have suggested that other immune‐modifying genes may also play a role in modulating lung fibrosis, through various mechanisms. For example, the rs5743890 polymorphism in the TOLLIP gene is associated with increased susceptibility to IPF, increased mortality and reduced expression of this protein, which normally functions as a negative regulator of TLR signalling.4 (LTB4) induced by injury. The presence of increased numbers of PMNs in the bronchoalveolar lavage fluid (BALF) portends a poor prognosis for IPF patients.4, can reduce the initial PMN inflammation seen in response to bleomycin and lessen development of lung fibrosis.In addition to innate immune receptors driving fibrotic pathogenesis, there is also evidence for participation by innate immune cells themselves. Neutrophils or PMNs are short‐lived effector cells that are recruited to sites of injury where they may contribute to lung injury and/or fibroproliferation via the release of proteolytic enzymes such as neutrophil elastase (NE). PMNs are recruited via the release of chemokines, particularly CXCL2/CXCL8, or leukotriene B−/− mice or mice treated with a NE inhibitor, sivelestat, had reduced levels of TGFβ.In vitro, NE has been shown to promote fibroblast proliferation and differentiation into myofibroblasts.2 (PGE2) in the lung.2 is a molecule we have previously shown to be an endogenous inhibitor of NETosis.It is also likely that the proteolytic enzymes released by PMNs help to activate other key fibrotic cytokines such as transforming growth factor (TGF)β because bleomycin‐treated NESilicosis is a fibrotic lung disease caused by toxicity due to inhalation of silica glass particles. PMNs are important for clearance of particulate matter from the lung, and PMNs are capable of phagocytising many different particle types, including silica.−/− bone marrow, the fibrotic pathology was worse and the number of inflammatory granulocytes, including PMNs was increased, along with higher levels of IL‐17 which as mentioned above can activate fibroblasts.The data discussed above suggest an important role of PMNs in generating tissue injury and driving fibrogenesis in models of noninfectious acute toxicity caused by bleomycin or silica. In the third model of pneumonitis and lung fibrosis that we are considering in this review, infection of mice at week 5 following a syngeneic stem cell transplant with γHV68 leads to robust chronic inflammation and fibrosis that is highly dependent on IL‐17.In addition to PMNs, pulmonary macrophages are also thought to play an important role in driving fibrotic pathology and this has been one of the most active areas of recent study. Typically recruited to initial sites of damage or infection by inflammatory signals arising from damage to AECs, pulmonary macrophages are thought to clear pathogens and debris and orchestrate further inflammation by the release of chemokines.hi monocytes were shown to enhance the development of fibrosis when adoptively transferred into bleomycin‐treated recipient mice.While the precise roles of different macrophage subsets in the development of fibrosis have not yet been fully elucidated, studies suggest that certain subsets found within the injured lung may be responsible for driving fibrosis. Monocyte migration appears to be important in fibrogenesis, as pulmonary fibrosis was absent in bleomycin‐treated mice lacking the monocyte chemokine receptor CCR2.+) is lost.lo macrophages as monocytic in origin, supporting the idea that bleomycin‐induced lung injury ablates TR‐AMs which are replaced by monocyte‐derived alveolar macrophages (Mo‐AMs) that migrate into the alveoli and upregulate Siglec F.More recently, reports have also highlighted the importance of a discrete subset of alveolar macrophages in driving fibrotic lung pathology.+ lung cells,It is likely that the magnitude of TR‐AM ablation dictates the composition of alveolar macrophages remaining following resolution of lung injury. For example, recruitment of Mo‐AMs was observed following diphtheria toxin depletion of CD11c−/− mice, which fail to recruit circulating monocytes, actually do worse.−/− mice, granulocyte accumulation is further enhanced with pathologic consequences.When considering silica‐induced fibrosis, macrophages are the cell type most characterised by inflammasome activation in response to silicaStaphylococcus and Streptococcus.Staphylococcus aureus and Streptococcus pneumoniae are common aetiological agents of bacterial pneumonia, indicating a tangible link between infection and IPF disease progression. The idea of bacterial infection promoting worse outcomes in IPF patients was further supported by the results of a small clinical trial testing the use of the antibiotic co‐trimoxazole. The study found that IPF patients treated with co‐trimoxazole contracted fewer respiratory tract infections and had significantly reduced all‐cause mortality.Another way the immune system may impact fibrosis is via regulation of infection and normal microbiota tone. Both empirical clinical evidence and epidemiological studies support a link between IPF and bacterial pneumonia and altered lung microbiota composition. A 2014 study found that IPF patients had double the bacterial burden isolated from BALF compared to healthy controls.In preclinical work that allows for more mechanistic insight, a striking observation was that germ‐free mice lacking an endogenous microbiome are protected from mortality following bleomycin‐induced fibrosis.Lachnospiraceae in the lungs of mice with pneumonitis and fibrosis. Interestingly, this family is a member of the Firmicute phylum and we have also shown that loss of Firmicutes in the BALF of human hematopoietic stem cell transplant patients that are experiencing pulmonary complications are associated with increased production of numerous pro‐inflammatory cytokines.We also recently analysed the alterations to the lung and gut microbiome within the murine bone marrow transplantation model of pneumonitis and fibrosis induced by γHV‐68 infection and found that while the process of transplant alone or viral infection alone caused transient dysbiosis, the dual hit was associated with sustained and profound reductions in lung microbial diversity, but there was not a lasting effect on gut microbial diversity.Streptococcus pneumoniae following development of fibrosis was shown to drive greater fibrotic progression than that in uninfected mice.2.Pseudomonas aeruginosa following bleomycin‐induced fibrosis did not result in fibrotic progression, highlighting the extreme complexity of potential host–pathogen interactions in the fibrotic lung.In addition to possible effects caused by changes to the indigenous lung community, there is also an experimental link between fibrotic development and infection with bacterial pathogens. Infection of mice with Pulmonary macrophages have the ability to drive immune responses to respiratory pathogens by actively phagocytising microbes and producing reactive oxygen intermediates, nitric oxide (NO), TNF‐α and interferons following stimulation.ex vivo treatment with agonistic anti‐LAIR‐1 antibodies.Collagen is the predominant component of scar tissue and is found in high levels in fibrotic lungs. Macrophages and PMNs have various ways of sensing collagen itself as well as extracellular matrix stiffness, and studies have indicated that the signalling pathways responding to these environmental cues can alter cellular function. Leucocyte‐associated Ig‐like receptor 1 (LAIR‐1), an inhibitory receptor that binds to native collagen, was shown to promote alternative activation of immunoregulatory, tissue‐restorative macrophages and inhibit pro‐inflammatory macrophage differentiation.in vitro administration of silica to macrophages and neutrophils decreases their viability, likely due to lysosomal disruption, and can limit their ability to phagocytise bacteria and to kill intracellular pathogens.Similarly, it has been known for more than 30 years that With regard to the γHV‐68 model of pneumonitis and fibrosis post‐transplant, the process of transplantation impairs the phagocytic and killing functions of the alveolar macrophages and PMNsWhen taken together, there is now a body of literature that clearly supports the important role of innate immune cells in stimulating tissue injury and fibrogenesis, but it also seems that innate immune cells residing in a fibrotic microenvironment may be less equipped to fight off pulmonary infection. We speculate that this two‐way signalling may be another mechanism that promotes the progressive nature of lung fibrosis whereby innate immune cells trigger initial injury, but then undergo reprogramming within the fibrotic niche that impairs host defence, allowing for infections or alterations to the microbiota that ultimately further damage and scar the lung.In this review, we summarise the known contributions of the innate immune system to fibrotic progression, highlighting the importance of PMNs and macrophages in driving disease in three unique models of fibrogenesis. The roles of innate immune pattern recognition receptors and inflammasomes were considered. We also discuss the direct contributions of PMNs and macrophages in both lung injury and driving fibroblast proliferation and ECM production to mediate aberrant wound repair. In addition, the role of microbial influences on disease  is examined. To conclude, we speculate upon how the ability of innate immune cells to respond properly to respiratory pathogens may be compromised following the development of fibrosis.Despite this compilation of research, much is still unknown about the precise roles of innate immune cells in fibrotic lung disease. While it is thought that fibrosis is perpetuated by injury to the lung, how PMNs fit into the picture is much less clear. Do PMNs drive the initial lung injury or is their presence in the lungs a response to an external stimulus (such as an occult respiratory infection) that initiates the injury? Are they needed for clearance of debris, or do they die in tissue via NETosis and necroptosis to promote fibroblast activation? If so, is this a common mechanism in all forms of tissue fibrosis?Macrophages are also known to play an important role in regulating wound repair; however, nonpathological wound repair terminates in a return to tissue homeostasis. What is it about the fibrotic microenvironment that dictates whether a macrophage adopts a tissue‐restorative phenotype transiently to allow a return to homeostasis versus becoming pathologically activated to promote fibrosis? In addition, the profibrotic function of the recently characterised Mo‐AM subtype has been suggested,Streptococcus pneumoniae following fibrosis actually increased fibrogenesis through cytotoxin‐mediated AEC death,Pseudomonas aeruginosa did not exacerbate fibrosis,Additionally, the complicated interplay between respiratory pathogens and innate immunity in the fibrotic lung is extremely understudied. As one study showed, infection with Pseudomonas aeruginosa may not drive the deposition of additional ECM following infection, they could be the cause of declining lung function in IPF patients due to the induction of inflammation and the inflammatory exudate further limiting gas exchange. This important complication has received relatively little attention in the field of IPF research as there has been a strong focus on studying the ‘noninfectious’ causes of acute exacerbations. Therefore, future effort should consider evaluating the interactions between respiratory pathogens and the innate immune system within the fibrotic lung to better understand how to treat these patients, and to understand that their immune systems may in fact be characterised by impairment, rather than overt activation in late stages of disease.Lastly, there is a preponderance of evidence to support the idea that the development of fibrosis alters the function of innate immune cells, possibly making IPF patients more susceptible to respiratory infections in the first place. It is well‐known clinically that IPF patients that acquire respiratory infections have very poor outcomes.The authors declare no conflict of interest.


The use of epigenome editing is set to expand our knowledge of how epigenetic landscapes facilitate gene expression capacity within a given cell. As epigenetic landscape profiling in health and disease becomes more commonplace, so does the requirement to assess the functional impact that particular regulatory domains and DNA methylation profiles have upon gene expression capacity. That functional assessment is particularly pertinent when analysing epigenomes in disease states where the reversible nature of histone and DNA modification might yield plausible therapeutic targets. In this review we discuss first the nature of the epigenetic landscape, secondly the types of factors that deposit and erase the various modifications, consider how modifications transduce their signals, and lastly address current tools for experimental epigenome editing with particular emphasis on the immune system. The completion of the draft sequence of the human genome in 2001 Epigenetics research is complicated by a number of factors: first, because epigenomes are cell type‐specific, a challenge has been to generate purified cell types in sufficient numbers to exploit technologies that can report on the landscape in an unbiased manner. Cell types that arise during early differentiation represent a particular challenge for isolation for both numerical and ethical reasons. In adults, while cell purification is relatively straightforward in mature immune systems, emerging information from single‐cell sequencing has begun to reveal an expanded repertoire of distinct cell types, as exemplified with subtypes of dendritic cells Certain immune cells are often considered to be phenotypically plastic A further challenge is technical, and derives from the fact that sequencing‐driven techniques such as ChIPseq and ATACseq enable population‐level analysis which need careful interpretation in order to determine for how many cells in that population the landscapes derived are accurately representative. Epigenome‐wide analysis from single cells and small numbers of cells is now the subject of numerous applications The ability to control transcriptional output of any cell is impacted at a number of levels. Experiments on higher‐order chromatin have started to reveal the complex communications that exist between chromosome domains and the establishment of chromosome territories within the nucleus The two primary determinants of epigenetic landscapes remain the histone code and DNA methylation. Consequently, the substrates are the histone proteins which constitute the protein component of the nucleosome and, predominantly, the cytosine : guanosine dinucleotide (CpG) of DNA. In this review, we refer only to the canonical targets, histones H2A, H2B, H3 and H4 and modifications thereof, but there is a large body of work studying replacement histones such as H2AZ and H3.3, let alone the linker histone H1, along with non‐canonical targets for DNA methylation.Understanding what effect specific post‐translational modification of histone proteins has upon gene expression capacity remains an active area of research Despite these challenges, expressed genes or genes for which expression is permissive upon receipt of appropriate stimuli within the cell tend to be marked epigenetically in a broadly similar way. Epigenetic landscapes can reveal capacity for both current and predictive future gene transcription compared to RNA signals, which are a record of either current or historical expression which remains in the cell until those RNAs are degraded. An average expressed gene would tend to display a complex pattern of histone modifications which includes but is far from limited to including trimethylation of lysine 4 on histone H3 at the nucleosomes that pack approximately 3 kb of DNA around the transcriptional start site (TSS) In terms of genes that are epigenetically silenced, histones associated with the transcribed region and 3' and 5' intergenic regions of DNA are often decorated by H3K27 and H3K9 trimethylation Cytosine methylation is the most prevalent modification of DNA. In canonical DNA methylation, methyl groups are added to position 5 of the pyramidine ring of deoxycytosine within the context of a CpG dinucleotide. The methylation status of CpG dinucleotides is not uniform among individual genes; rather, CpGs show position‐specific variation in methylation. While the DNA regions proximal to TSSs of genes that are permissive for transcription tend to be depleted of DNA methylation, the areas flanking the TSS may display a greater degree of variation in methylation It is likely is that these two gross transcriptional states, being epigenetically silenced or actively transcribed, represent the extremities of the possible gene expression potentials, and an individual gene in any given cell is unlikely to be able to switch easily and rapidly between the two. Variation of transcriptional activity may reflect different regulatory domains being revealed or not revealed in distinct cell states. Alternatively, or additionally, transient expression of key transcription factors such as Jun, Fos and nuclear factor kappa B (NF‐kB) might act upon and modify further a chromatin landscape that is already broadly permissive for transcription.One of the key advances to understanding the causal role of epigenetic landscapes on gene expression and cellular phenotype has been the identification of proteins that deposit, remove or signal transducers of histone and DNA modifications, the so‐called writers, erasers and readers of the epigenetic codes.Su(var)3‐9, Enhancer‐of‐zeste and Trithorax) domain allowed the enzymes that methylate distinct lysine residues in histones to be characterized The identification of the SET , a flavin‐containing amino oxidase, was the first enzyme identified that had the ability to demethylate mono‐ and dimethylated histone H3 lysine 4 histone substrates Both histone acetyl transferase and deacetylase families are characterized by their sequence homologies. There are upwards of 30 distinct proteins in humans with histone acetyl transferase activity, a catalytic activity that transfers an acetyl group from acetyl coenzyme A (CoA) to the ε‐amino group of a histone lysine residue. Some of these proteins can also use crotonyl CoA as their substrate. These HATs are categorized into families, first by their cellular distribution, which comprises either nuclear or cytoplasmic HATs. The nuclear HATs are categorized further by structural homology into three main groups, the GNAT (GCN5‐related N‐acetyltransferases) +‐dependent Four classes of histone deacetylase (HDAC) proteins have been identified, and these classes are again demarcated based upon sequence homologue. Class I HDACs tend to be expressed ubiquitously and compartmentalized to the nucleus de novo and maintenance DNA methylation. DNMT1 is the key maintenance methyl transferase utilizing hemimethylated DNA as its substrate, but can also undertake de‐novo methylation. DNMT3A and B are both de‐novo methyltransferases but have a lower activity than DNMT1 The three mammalian DNA methyl transferases (DNMTs), DNMT1, 3a and 3b, catalyse The ten‐eleven translocation methylcytosine dioxygenase (TET) family initiate a chain of reactions that can ultimately demethylate 5 methylcytosine ), demonstrating that both reader and writer functionality can reside within the same protein. In addition, histone and DNA‐modifying proteins assemble into multi‐protein complexes such as Complex of Proteins Associated with Set1 (COMPASS), SAGA and polycomb. In terms of DNA methylation, both methylated and unmethylated CpG dinucleotides are recognized by specific binding proteins. MBD (methyl‐binding domain‐containing) and methyl CpG‐binding proteins (MECP) recognize methylated DNA Many of the writers and erasers of histone and DNA modifications have additional motifs outside of their catalytic domains which are responsible for the targeting of the protein to chromatin. These domains include chromodomains which recognize methylated histones, bromodomains which recognize acetylated histone, plant homeodomain (PHD) fingers, TUDOR and WD40 domains  regulatory domains were targeted with either dCas9.TET1 or dCas9.p300 catalytic domains in order to demethylate or deposit H3K27acetylation. While altered DNA methylation did not display a potent effect, histone acetylation promoted FoxP3 expression and induction of FoxP3 target genes in vivo to those areas by mass spectrometry or immunological investigations While fusion proteins of catalytic domains coupled to dCas9 can be used to deliver a particular histone or DNA modification artificially onto a chromatin template, they do not address how, in diseased cells, the altered chromatin landscape initiates, what transcription factors are differentially recruited and precisely which enzymes are the propagators of the altered landscape. These altered landscapes can, however, be interrogated to determine transcription factor binding‐site enrichment. To further this process of factor identification, epitope tagged dCas9 may also be used as an immunoprecipitation reagent, where guide RNAs provide the targeting capacity to specific regions of fragmented chromatin enabling unbiased analysis of the proteins that are recruited CRISPR.Cas9‐mediated epigenome editing is beginning to be employed to understand the epigenetic constraints upon gene expression, and in particular the impact of altered epigenomes in diseased cells. For such studies, however, numerous considerations arise. What is the cell type of interest? Is it possible to isolate those cells in health and disease? How many subjects should be studied? Are there distinct endotypes of disease that must be considered? Is there likely to by an impact of SNP variation on disease? Which histone modification should be studied? With the emergence of technologies permitting analysis of either single or few cells, this field of research is likely to be fertile, as the focus of analysis shifts from descriptive to analysis of functional consequence.The authors declare no competing financial interests.


The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.Dear Editor,We thank Dr. Alonso et al for their commentary“Substantial” vs “high” burdenWhile we noted that there is substantial burden from influenza virus infection in Bangladesh in 2010‐2012,Influenza burden in tropical climate countriesThe authors made general comparisons between tropical and temperate climate countries and indicated that there is a lower burden of influenza disease in tropical climate countries. However, we are not convinced that this comparison is generalizable to all tropical countries. For instance, not all tropical countries have year‐round influenza virus circulation as the authors suggest, including Bangladesh and Rwanda.The effect of the influenza A(H1N1)pdm09 virus on mortalityIn their comment, the authors implied that the 2009 influenza A(H1N1) pandemic virus did not affect mortality in tropical climate countries. However, global mortality studies have shown that the 2009 influenza A(H1N1) pandemic virus did in fact affect mortality in tropical climate countries.Poor match in timing of respiratory deaths and influenza circulationD/P) by the monthly proportion of influenza‐positive specimens (F) and then added for a consecutive 12‐month period to produce the annual estimates. If for a given month, the proportion of samples testing influenza positive was zero (ie F = 0), ARI deaths (D/P) from that month would not be attributed to influenza nor contribute to the annual mortality rate estimates as multiplying the ARI deaths by 0% influenza positive (D/P * F) would also be zero. Thus, the estimates for Bangladesh did account for the offset between virus circulation and ARI mortality.The authors note that there was dissociation of peaks of influenza virus circulation in the sentinel surveillance data and acute respiratory illness (ARI)‐associated mortality in the catchment areas in the months of December‐February in Bangladesh. We too observed this offset and considered it in our analytic approach to estimate influenza‐associated ARI deaths for Bangladesh. In our methods, we calculated the influenza‐associated mortality incidence using monthly ARI death counts and the monthly proportion of samples that tested positive for influenza viruses. As stated on page 67 of our article (the equation),Mortality or hospitalization attribution to other underlying conditions or pathogensThe authors also note their concern that we may be attributing influenza virus infections to deaths among persons with preexisting conditions or terminal illnesses. In the survey for all age groups in Bangladesh, the decedents must meet the case definitions as defined in the article and “the disease had to be a new onset and not a progression of a pre‐existing condition.Furthermore, we agree that RSV surveillance and burden estimates are very important to consider in these settings.Comparison with IHME estimatesThe authors also compared our estimates to those estimated by the Institute for Health Metrics and Evaluation (IHME). The IHME methods for estimating global influenza deaths focus on attributing influenza virus infections to lower respiratory tract infection deaths,We would like to thank the authors for their discussion of our papers.


Adverse events occur in health care. Detection and reporting of deterioration therefore have a critical role to play. Patient and family member (consumer) involvement in patient safety has gained powerful support amongst global policymakers. Few studies, with none taking a rigorous qualitative approach, have drawn upon consumers’ experiences to establish their preferences in consumer reporting of patient deterioration programmes.To explore consumers’ experiences of previous reporting of patient deterioration; their preferred educational strategies on this role and recommended pathways in a consumer reporting of patient deterioration model.An interpretive, qualitative research design was utilized. Nine focus group interviews were undertaken across Adelaide, capital city of South Australia. Interviews were audio‐taped, transcribed and analysed thematically. Twenty‐six adults described, then reflected, on previous experiences of reporting patient deterioration.Overarching themes incorporated consumers’ experiences and patient/family education. Three themes emerged in relation to consumers’ experiences: feelings, thoughts and actions. Five themes arose on educating consumers: content, timing, format, information providers and information recipients. The consumers’ deep reflections on their past reporting experiences led to the development of a new model for consumer reporting of patient deterioration.Consumers’ views on ways to improve consumer reporting of patient deterioration processes emerged. These improvements include structured educational programmes for staff advocating open health‐care professional/consumer communication, educational materials developed and tested with English‐speaking and culturally and linguistically diverse consumers and a model with three consumer reporting pathways. At the very least, adverse events have led to patients enduring preventable complications, unanticipated transfers to Intensive Care Units, longer hospital stays and diminished capacity for independent living.Detection and reporting of deterioration A review of evaluative studies undertaken after implementation of a range of consumer reporting of patient deterioration programmes (CRPDP) has indicated consumers can potentially detect and report patient deterioration to RRS.26,27 When considering this issue, no studies were found that drew on consumers’ experiences of reporting deterioration to establish their preferences in components of CRPDP.In the past, health professionals have taken the lead role in development of CRPDP often responding to family demand following tragic, preventable consumer deaths, for example, Josie King.2To explore consumers’ experiences of previous reporting of patient deterioration; their preferred educational strategies on this role and recommended pathways in a consumer reporting of patient deterioration model.3An interpretive, qualitative research design that incorporated focus group methodologyA purposive sample of participants was sought through community‐based consumer organizations. These organizations shared short articles with members, seeking volunteers for the study. Adults who had been patients or family members of past patients admitted to Australian acute hospitals were sought. Potential volunteers were required to have had experiences of reporting deterioration within 5 years of the commencement of the study. Individuals who had been previous in‐patients for obstetric or mental health reasons were not included as their needs were seen as specialized.Nine focus groups were undertaken by health‐care researchers experienced in qualitative research methods. Each group was led by one of the three facilitators: a Masters‐prepared hospital‐based quality improvement manager and two University‐based PhD‐prepared senior academics with clinical expertise in cardiovascular and acute surgical care. The 60‐ to 90‐minute interviews were held in hospital or University meeting rooms across Northern, Southern and Central Adelaide settings and via a teleconference for those unable to physically attend. Only research participants and research team members were present at each focus group. Three of the focus groups included both patients and family members, one involved patients only, and five groups were made up of family members only.The focus group interview approach was based on related literature and guided by Hofmann et alThe focus group interview topic guide was designed to elicit a comprehensive understanding of the patient or family member's experience Table . The focThe focus group interviews were audio‐recorded, transcribed by a professional transcriber and de‐identified as “FG” 1‐9 with pages numbered. The basis of each focus group's discussion was the participants’ recollections and subsequent responses to each other's comments. Interview transcripts were therefore not sent to participants. Previous in‐patients were identified within the transcripts as “P” (n = 9) and family members of in‐patients as “FM” (n = 17).Six phases of exploratory thematic analysisThemes were reviewed in relation to phrases used by individuals and compared across the interview data set. Preliminary thematic mapping then commenced (phase four). Refinement of the themes occurred through re‐reading of participants’ experiences and reflections. Data saturation occurred when no new emergent themes or subthemes were noted following analysis of all of the interviews (phase five). Two overarching themes were clear, related to the participants’ experiences when reporting deterioration and reflections on patient/family education on their potential role in reporting of patient deterioration. Themes related to consumers’ experiences incorporated feelings, thoughts and actions. Themes associated with patient/family education included content, timing, format, information providers and information recipients. Finally, the participants’ preferences on how to improve the process of reporting deterioration by patient or family member generated a new model for consumer reporting of patient deterioration (phase six).Guba and Lincoln4Twenty‐six (26) participants (19 women and seven men) volunteered. The participants included 17 family members and nine patients who were residents of metropolitan Adelaide or nearby regions of South Australia. Ages ranged from 27 to 86 years, providing perspectives across generations. A profile of the patients’ reason for hospitalization (when known) and nature of deterioration episodes has been summarized in Table During the interviews, participants described occasions involving either themselves or a family member's deterioration requiring rapid medical intervention. The emergent themes focused on Consumers’ experiences when reporting deterioration and Patient/Family education—information on recognition and reporting of patient deterioration. A model for consumer reporting of patient deterioration was also developed subsequent to the initial thematic analysis. The two themes are presented first in the results section followed by a description of the new Model.4.1This theme has been constructed from the consumers' feelings, thoughts and actions which have been described below, accompanied by evocative responses .4.3.I thought I would be alright, they looked like they knew what they were doing; it was the best place to be When considering the health professional's response to their report of deterioration, some participants, like the patient below, held positive thoughts about the clinician's assessment and provision of the necessary care..They're way understaffed, rushed off their feet. I found it hard, I just felt like a burden, I didn't want to buzz Others were uncertain about how to engage with clinicians to gain fast action, describing their thinking as dependent and powerless, perceiving the health system as under resourced with weak care coordination..[the] Nurse kept going back to the senior who realised I was making a bit of a fuss and said ‘do you want a MET call for a relative’. Luckily I understood what she meant and said yes Contrastingly, some decided to try to take control of the situation. These participants drew on their medical knowledge to successfully escalate concern about the patient. Confident participants sought advice from the senior nurse and, as a result, gained collaborative involvement in decision making on the need for a call to the rapid response team. As one commented:.I felt very torn between believing that these are professionals, they must know what they're doing, we just have to trust them, and seeing what I was seeing in front of me, and seeing that incongruity between people telling us that it's okay and that it's not looking okay, it's actually looking worse than I've ever seen it Some participants described an eventual loss of trust when they thought clinicians were not addressing their concern. As one participant said:4.4.If I hadn't known people…the rapid assessment team came because my friend [spoke up]. I don't know what would have happened. Time was a big thing with [child's] illness The participants’ actions after reporting deterioration were diverse. Some described taking no further action beyond reporting their concern. Others drew on their own knowledge and skills to seek action through the system. Several participants described tapping into their own personal network for guidance on gaining further treatment..I wrote a letter of complaint and got a reply. They did say that it was wrong, they're now using my case as a blind study. [but] The letter is really saying, ‘there, there dear, it's alright, nobody else will get treated the way you did’ A number of participants eventually lodged formal complaints in regard to their efforts to report patient deterioration. As one patient stated:4.5what information should be conveyed” (Content), “when the information should be given” (Timing), “how the information should be given?” (Format), “who should provide the information” (Information providers) and “who should receive the information” (Information recipients).The participants then offered their perceptions on the most effective ways to inform consumers on their potential role of reporting deterioration Figure . This th4.6The participants felt the position of the consumer to report should be made clear in the content of the information provided. A simple flow chart of steps to follow to obtain further assistance, clear details on who to call when raising concerns and what to expect from clinicians responding to their concerns were sought. As one patient described, content should be “Simple [in order] to make it easy to read and absorb” .4.7The consumers wanted to receive the information on admission, regularly during their hospital stay, and at strategic times when patients and family members could fully comprehend, that is, where they were in a receptive cognitive and emotional state. Typically, as one patient stated: “On admission when family members were waiting, would be an ideal time” .4.8Verbal explanation, considered paramount, participants described the struggle to process printed information when feeling distressed, necessitating verbal communication. Print format, as brief information to support verbal explanation, was favoured. Video materials were very popular through a range of devices and platforms. Videos were recommended for adults and children in the form of real life‐experiences or realistic role plays where consumers successfully reported and received assistance for patient deterioration. Posters were deemed related to printed information but thought to function differently. Consumers sought their strategic placement in patients’ rooms, wards, waiting rooms and toilets. Mobile technology through smart phones and tablet devices were seen as an excellent medium to enhance the communication process through various approaches . Other forms of communication included alternate verbal and written formats for accurate information. Overall, participants suggested that hospitals needed to be “sensitive to knowing when people are cognitively and emotionally ready to receive information” .A multimedia approach was recommended, incorporating communication methods that would reach across cultures and age groups. Consumers with low health literacy were seen as particularly vulnerable. Participants wanted information presented positively, leading them to feel safe. Preferred multimedia modes included: 4.9Nursing and medical staff were the preferred professionals to provide information on the consumer's potential role in reporting deterioration. However, further education of health professionals to enhance effective communication with consumers was recommended. Key communication skills sought in health professionals were their ability to: listen and acknowledge family member's knowledge of the person; respect for the consumer's ability to provide vital contextual information; give clear explanations and feedback on the patient's condition ; clarify family members’ potential roles; choose the right time to communicate and ensure a senior clinician assess the patient.Nurses were seen as the preferred professional to provide information to consumers; nurses currently on the shift were seen as responsible for taking on that initiative.liaison” and “nurse” were used together with a specialist nurse liaison recommended. The consumers sought access to a patient liaison or advocate with advanced assessment skills as someone they could turn to who also had in‐depth knowledge of the health‐care system..A liaison to turn to [would be helpful] as it's a big decision to make when you're feeling disempowered At times, the terms “Medical and other health‐care professionals were also seen as potentially effective providers of information; doctors for medical‐related questions. Participants described the need for other forms of assistance, particularly in situations that were less urgent. For example, social workers to handle family resource needs and chaplains for spiritual support. As one family member commented: “Social workers are better equipped to handle family members and find resources” .4.10patient should always be informed and able to nominate a family member or friend to receive information about their potential role in reporting patient deterioration. For example, one family member viewed this formal recognition in the health system as important so the nominee “can recognise when they're getting sicker and press the button” . Participants also recommended respect for power of medical attorney, allowing that person to access information and advocate while the patient was incapacitated.Participants felt that the 4.11You're Worried, We're Listening” that emerged from the consumers’ comments. This catchphrase exemplified their desire for respectful, two‐way communication when reporting their concerns about patient deterioration to health professionals. The proposed model . A health‐care professional in a liaison role from within the hospital but outside the ward/unit setting was recommended. Critical care‐based nurse responders with advanced life support skills and a designated role to assess patients at the bedside and activate the RRS team as needed have been utilized in outreach models.To be satisfied with the overall process of CRPDP, family members wanted their reporting to elicit rapid skilled treatment to address reversible clinical patient deterioration. Importantly, the consumers were well aware that patients may die during critical illness or be faced with a transition into end‐of‐life care.5The aim of this study was to investigate consumers’ past hospital experiences to inform development of a consumer‐directed model for reporting patient deterioration. This study explored consumers’ experiences of reporting previous patient deterioration; consumers’ views on consumer‐targeted educational information on reporting patient deterioration; and the preferred processes for consumers to report and escalate care for a deteriorating patient.In regard to communicating with health professionals, our findings were consistent with previous research indicating the reticence of consumers to “speak up” on patient safety concerns in health‐care.Effective consumer/health‐care professional communication has become known as crucial to the achievement of patient safety.Our proposed consumer reporting model starts with the education of the consumers  in quantitative terms, the participants ranged in age, gender and residential location providing potentially diverse views through rich qualitative data. Transferability of these findings rests on the meaningfulness of the consumers’ perspectives to others in similar settings.5.2The proposed model has the potential to be used within departments of health policy to guide consumer reporting of patient deterioration programmes required by national safety and quality health‐care service standards in Australia and other developed countries.6The outcomes of this study have shown that based on experience consumers have strong opinions on how reporting of the deteriorating patient can be improved. These improvements include structured educational programmes for staff advocating open health‐care professional/consumer communication, educational materials developed and tested with English‐speaking and culturally and linguistically diverse consumers and a model with three consumer reporting pathways.None of the authors have conflicts of interest. Click here for additional data file. Click here for additional data file.


GARS (glycyl‐tRNA synthetase) gene was identified.Charcot‐Marie‐Tooth (CMT) disease is a very heterogeneous neurological condition with more than 90 reported genetic entities. It is the most common inherited peripheral neuropathy; however, cases are rarely reported in sub‐Saharan Africa. In addition, only few families, mostly of Caucasian ancestry, have been reported to have Charcot‐Marie‐Tooth disease type 2D (CMT2D) mutations. To date no case of CMT2D was reported in Africa. We present here a consanguineous family with CMT phenotype in which a novel mutation in the PMP22 duplication and mtDNA). Putative mutations were verified in all available family members to check for segregation.Patients were examined thoroughly and nerve conduction studies (NCS) were performed. DNA from the proband was used for CMT gene panel testing  in the This is the first report of a genetically confirmed CMT2D case in Africa, expanding its genetic epidemiology. Increasing access to genetic testing may reveal more novel CMT variants or genes in the African population that could be relevant to other populations and further our understanding of their mechanism. It is characterized by a progressive demyelination or axonal degeneration and cell death resulting in distal muscle weakness and atrophy and sensory loss. Charcot‐Marie‐Tooth disease type 2D (CMT2D) is a classic axonal peripheral sensorimotor neuropathy characterized by weakness and atrophy of more upper than lower limbs involving mostly thenar and first dorsal interosseous muscles. Earliest symptoms in many individuals include transient cramps and pain in hands and calf muscles on exposure to cold or exertion. Sensory loss may affect all modes and can be variable within and across families. The disease is caused by mutations in the glycyl‐tRNA synthetase  analysis was done first, and then a Next‐generation CMT gene panel testing composed of 50 genes and the mtDNA  including GARS gene (GenBank accession number: NG_007942.1) was performed on the index patient. The putative mutation was verified in SNP databases to exclude rare variants, and was checked in all available family members. In silico analyses with PolyPhen, I‐Mutant and SIFT were performed for deleteriousness.All of the individuals included in the study were evaluated by a group of neurologists after giving consent. Blood chemistries including glucose and vitamin B12 levels were done to exclude common acquired causes of polyneuropathy. Nerve conduction studies (NCS), ENT and ophthalmologic examinations were done to assess peripheral nerve, ear, or ocular involvement. DNA was extracted from peripheral blood in all available family members for genetic analysis. 3GARS gene at position c.794C>A, leading to the amino acid change Ser265Tyr (Figure The patients are from a consanguineous family of Bambara ethnicity, and two out of the five living siblings presented with distal muscle weakness and atrophy Figure a. Familyr Figure b. Sequenr Figure c. In add4GARS gene have been found in a relatively small number of families from different populations in Europe, North America, and Asia (Liao et al., GARS gene have also been shown to cause dSMA‐V, an early onset of pure motor neuropathy. While no CMT2D case was reported in Africa, dSMA‐V has been reported in a family with North African origin (Dubourg et al., Charcot‐Marie‐Tooth disease type 2D caused by mutations in the GARS causing CMT2D in a Malian family. CMT2D is an autosomal dominant disease with high intrafamily variability, and most of the patients present symptoms during the second decade (Sivakumar et al., We report here a novel mutation in Glycyl‐tRNA synthetase is a member of the aminoacyl‐tRNA synthetase family. The human GARS protein has three major functional domains including the core catalytic domain located at the 92nd–168th residues and the 241st–324th residues where the mutation reported in this study is located (Rohkamm et al., GARS mutations have weak genetic and functional evidence of causing CMT (Griffin et al., Some GARS, expanding the genetic epidemiology of this CMT subtype. The Ser265Tyr variant, which was not previously reported elsewhere, adds to the limited number of GARS disease‐associated variants. Although some clinical variability has been published in CMT2D families, the clinical pattern seen in the family presented in this study has rarely been reported. This can be stochastic or due to other genetic or environmental modifiers. Larger cohort studies in Africa will allow phenotype‐genotype studies to understand the phenotypic variability and the underlying mechanism distinguishing CMT2D from dSMA‐V. Such studies may also uncover other new CMT variants or genes that can be studied in other populations.We report here the first CMT2D cases in Africa and a novel mutation in The authors declare that they have no conflict of interest.


This paper examines how established firms use their core competences to diversify their business by exploring and ultimately developing green technologies. In contrast to start‐ups dedicated to a green mission, diversifying into green markets by developing new products based on existing core competences has proven to be challenging. This is because the exploration processes to find a match between green technology opportunities and internal competences is complex and new to most established firms. This paper gains insights into exploration processes for green technologies and the learning modes and outcomes linked to these processes. We examined exploration processes at the microlevel in an embedded case study of an engineering firm using a combination of the “fireworks” innovation process model and organizational learning theory. First, we found that developing green technologies involves a long‐term exploratory process without guarantee of (quick) success and likely involves many exploration failures. Second, as exploration unfolds along multiple technology trajectories, learning occurs in individual exploration paths (on‐path), when new paths are pursued (path‐initiation), and when knowledge from one path is spilled over to subsequent paths (across‐paths). Third, to increase their chances for success, firms can increase the efficiency of exploration by fostering a failure‐friendly organizational culture, deliberately experimenting, and purposefully learning from failures. The path‐based view also shows the inherent complexity of green technology innovation. (c) By discussing two key innovation practices—deliberate failures and intelligent trial and error—that can be managed to increase chances for success.The remainder of this paper is structured as follows: Chapter 2 reviews the literature on green innovation and organizational learning. Chapter 3 presents the methodology and introduces the embedded case study. Chapter 4 analyses the learning outcomes, and Chapter 5 concludes the paper by discussing how a conventional firm can explore green technologies and markets and how this exploration can be managed.22.1Green innovations include new technologies, products, services, or business models that have positive impacts on the environment and society  set of activities for new product managers to follow. Such models are clearly unrealistic: product innovation simply does not occur that way, and normative guides that do not recognize either the differences in processes or the overlapping nature of activities will probably meet with little success.Few analytical models embrace the complexity of the innovation process described by Cooper. This explains why this research uses the fireworks innovation process model which allows to study green technology innovation processes without reducing their complexity. The model was already successfully used in German literature to examine cases of sustainability innovation , and organizational learning are used to build our preliminary conceptual framework  is a good representative for radical innovation in resource‐constrained contexts. In their systematic literature review, Klewitz and Hansen  found thWe conducted theoretical sampling  that are sold to manufacturers of machine tools (its primary market), turbines, or various other industrial machine manufacturers. Product development typically takes several months and is characterized by intensive research and development collaboration with customers and trust‐based, long‐term relationships. Production is typically done in small batches and is, contrary to industry trends, fully located in Germany. Sales offices exist in Europe, the United States, and Asia. Top management, knowing that new path‐breaking technologies might weaken its main market segment  sometime in the future, recognized the urgency for exploring new product and market areas. Inspired by their intrinsic motivation for sustainability  to develop new applications for the market of renewable energy technologies  loop learning outcomes relate to the innovation paths in three ways Table : first, 4.14.1.1Even though not all innovation paths led to successful commercialization, they generated important knowledge about new green technologies and markets. As will be later analyzed in detail, it is this on‐path learning which also becomes useful to exploration of subsequent innovation paths (see T2). First, the firm added new technologies to its technological repertoire. On path P1, it discovered the feed‐in technology that allowed it to transform renewable energy to fit grid characteristics Table .Second, on each path, the firm also learned about new market environments Table : the aut4.2Learning outcomes allowed the firm to set out on new innovation paths that would not have been considered if they had not explored previous paths. In this regard, two learning outcomes played an important role: first, the identification of new technology‐market areas; (Learning 2) and second, the adjustment of the size of the innovation space (Learning 3).4.2.1One of the most striking findings is that the exploration of a technology‐market area allows the firm to identify other—different but still related—green technology‐market areas and can thus open subsequent innovation paths. It appears that the discovery of new areas is path‐dependent on the technology and market knowledge gathered on the earlier paths Learning 1). Consequently, even if a path leads to a setback, the discoveries made can allow a firm to identify new and promising paths. For instance, discovering how the automotive market (P1) works  allowed TechLtd to recognize the market opportunity of flywheels as onboard storage in heavy‐duty vehicles (P3). In fact, as explained in Learning 1, the feed‐in technology discovered on Path P1 allowed the firm to enter other SET markets. Exploration on all subsequent paths was thus conditional on having embarked on path P1  and later small wind turbines (P2). This selection significantly narrowed down the innovation space. When it experienced difficulties penetrating these markets, TechLtd again widened the space from alternative energy generation (P1 and P2) to energy storage (P3), and finally even more broadly to energy‐efficient technologies (P4). Although the innovation space was widened in this second phase, the decision to develop components that merely increased the efficiency of existing technologies (rather than engaging with high‐impact innovative technologies) implies that TechLtd's initial ambition to develop sustainable technologies strongly decreased, and hence its potential sustainability impact. Thus, over time, the firm became more realistic with regard to its level of sustainability ambition.4.3In addition to learning how to initiate new paths, double‐loop learning also allowed the firm to reflect how exploration is done and draw important lessons for future innovation management practice. This reflection at the metalevel involved three learning outcomes. First, the firm came to understand the need for in‐depth market exploration (Learning 4). Second, it increased its portfolio of exploration methods and became proficient at selecting the appropriate one (Learning 5). Third, it learned to make exploration more efficient (Learning 6).4.3.1The firm learned across paths about the importance of market exploration—including end users—in assessing the validity of new business ideas before significantly committing resources. In‐depth market exploration is particularly important in the context of emerging technologies with poorly established markets, a situation typical in the renewable energy context . Indeed, the dynamics of early‐stage markets are more complex . On Path P3, TechLtd sought for the first time to (a) actively find new customers on its own, (b) attended a workshop to sense the pulse of the emerging industry, and (c) approached leading end users (not customers) with the aim of understanding their needs and so the viability of end‐user business models in a highly volatile the market . Improving exploration efficiency allows a firm to increase its overall chances of success, as it is able to “walk down” more paths, increasing the chances that one will lead to success. The findings show an evolution from a random to a more intelligent trial‐and‐error approach, with exploration activities yielding better learning outcomes. This evolution is most visible from Paths P2 to P4 with regard to three elements.First, the findings show that the effort needed to assess a new business idea decreased in terms of the number of exploration activities needed, the duration of the exploration, and the financial resources involved Table . For insSecond, the firm improved at selecting the appropriate exploration methods, making it more efficient at exploration. Indeed, across paths, the use of exploration methods became more targeted and yielded more accurate information. The proficiency at selecting the appropriate method increased along path P3. Fewer methods were used, but they brought exactly the information needed to understand the market dynamics. As the market was not mature, top management terminated this path early on without significant investment Table . TechLtdThird, the decision whether or not to pursue an innovation path came earlier and was more pragmatic Table . Interes55.1This paper empirically examines how green (technology) innovation processes unfold at established firms aiming to seize new business opportunities emerging with sustainable development  cannot really be avoided. However, the failures related with T3 represent an important leverage point to improve the effectiveness of this process. We therefore focus on two significant ways to improve exploration: first, by fostering an organizational culture that values failures, and second, by developing exploration skills that yield a high return on learning.First, a safe exploration space can be created within the organization (Raisch, Birkinshaw, Probst, & Tushman, Second, the return on learning from each exploration activity can be increased (Birkinshaw & Haas, A failure‐friendly space and intelligent trial‐and‐error learning can help overcome the additional complexity that green technology innovation involves and thus represents a good basis for building green exploration capabilities. Given how new and different this is from managing the core business, hiring an external, qualified person to facilitate this exploration is possibly a very good investment for firms aiming to navigate the innovation journey.5.4An interesting question for future research is how a firm orients its initial search direction. Noci and Verganti  suggest 5.5The main limitation of this research relates to its research design. We studied a single firm and our results are therefore not simply generalizable. Nevertheless, they are transferable Guba,  as the lAlthough we did include external actors in our analysis, a second limitation comes from the firm internal perspective on the learning process. Future research could adopt a broader focus that approaches the innovation process from a network perspective, for instance, using the notion of action‐learning networks (Clarke & Roome,


Promotion of breast milk substitutes (BMS) and inappropriate marketing of commercially produced complementary foods (CPCF), including through television, can negatively influence infant and young child feeding. The World Health Organization International Code of Marketing of Breast‐milk Substitutes and subsequent relevant World Health Assembly (WHA) resolutions prohibit such advertising and require manufacturers and distributors to comply with its provisions; however, such regulations at national level may vary. Advertisements require Ministry of Health approval in Cambodia but are not regulated in Senegal. Television stations were monitored for 13 months in Phnom Penh and for 3 months in Dakar to assess advertisements for BMS and CPCF. Ten television channels (out of 16) in Phnom Penh and four (out of 20) in Dakar aired advertisements for BMS. Three and five channels, respectively, aired advertisements for CPCF. All BMS advertised in Phnom Penh were for children over 1 year of age. BMS products for children 6+ months of age and 1+ years of age were advertised in Dakar. Average air time for BMS advertisements was 189.5 min per month in Phnom Penh and 29.7 min in Dakar. Air time for CPCF advertisements averaged 3.2 min per month and 13.6 min, respectively. Fewer than half of BMS advertisements and three quarters of CPCF advertisements explicitly stated an age of use for products. Nutrition and health claims were common across BMS advertisements. This study illustrates the need to adopt, regulate, monitor, and enforce legislation prohibiting BMS promotion, as well as to implement regulations to prevent inappropriate promotion of CPCF. Advertisements for breast milk substitutes aired frequently on television channels in Phnom Penh (Cambodia) and Dakar  from September 2013 to September 2014. In Cambodia, these advertisements can only be broadcast with Ministry of Health/Ministry of Information approval; such approval was indicated on nine out of 11 advertisements. These advertisements contravene the World Health Organization's International Code of Marketing of Breast‐milk Substitutes.Fewer than half of the breast milk substitute advertisements observed provided an age of use for the product, and 14 out of 16 had at least one nutrition or health claim.One quarter of commercially produced complementary food advertisements in Phnom Penh and Dakar failed to state an age of use for the products. Recent World Health Organization guidance states that such products must not be promoted in a way that suggests they are appropriate for feeding an infant under 6 months of age.Nutrition and health claims were commonly made in advertisements for CPCF products. World Health Organization policies prohibit such claims on these products.Both Cambodia and Senegal should revise existing legislation to ensure that all provisions of the International Code of Marketing of Breast‐milk Substitutes and subsequent relevant WHA resolutions are implemented in full and that legislation also reflects the World Health Organization Guidance on Ending the Inappropriate Promotion of Foods for Infants and Young Children.1Promotion of breast milk substitutes (BMS) has been shown to negatively affect breastfeeding practices throughout the world  resolutions prohibits the promotion of BMS WHO, , includiThe inappropriate promotion of foods for infants and young children has been an ongoing concern among member states at the WHA . The three cable channels were chosen because their content was aimed at the entire family, and they were considered attractive to young mothers. All channels were broadcast in Khmer. Six out of 12 local channels in Dakar were identified as having viewership by at least 80% of Senegalese households and so were included in the monitoring. Out of the 30 most‐watched international cable channels in Dakar, an additional 14 channels were selected for monitoring as the media firm experts suggested they were likely to be watched by mothers of young children (n = 20). Of these 14 international channels, 10 were broadcast from France, two from Mali, one from Ivory Coast, and one from Cameroon. In Dakar, international channels were broadcast in French.All 13 local channels in Phnom Penh and three out of 13 international cable channels aired in Cambodia were included in this study , was not considered to be a suggested age of use unless an age  was also visually or verbally stated.Advertisements were reviewed and information logged on the date, time of day, duration (in seconds), product category, manufacturer and brand. A transcript of the recording was linked to each advertisement. Each different advertisement was transcribed in Khmer or French and then translated to English for assessment of its content by the researchers. All advertisements were observed and transcripts reviewed to assess which products were included in the advertisements and to determine if suggested ages of use for the products were provided either visually or verbally. Research has shown that different manufacturers use numbered “stages” to refer to different recommended ages of use for BMS products, but that these are not consistent across manufacturers  duration of the advertisement (the cost is determined in part by the number of seconds for the advertisement), (b) channel used , (c) day of the week (Monday–Sunday), (d) time of day, and (e) date . The media firm had access to fee schedules for all channels monitored. These fee schedules were used to determine the estimated cost for each advertisement aired which included the cost of advertisements by the time of day and day of the week reported in US$.Because only international cable channels aired advertisements in Dakar, no information is available on costs specific to Senegal because the fee schedule for these channels included the total price for an advertiser to air in all countries reached by the channel.33.1Table There were 11 BMS advertisements for specific brands/products in Phnom Penh and five in Dakar Table .Two BMS advertisements out of the five observed in Dakar verbally or visually gave the age of introduction for the product. Three of the 11 advertisements for specific BMS products did so in Phnom Penh; although numbered stages used to differentiate products were shown on the labels of all but one product (Abbott Pediasure), the associated ages were not visible. One label (Friesland Campina Dutch Lady) showed 1, 2, 3 on the label with no indication in the advertisement what these numbers indicated.“… with L comfortis, DHA, 23 types of vitamins and minerals, for growing and development.” (BMS advertisement from Phnom Penh).“… it contains essential nutrients including a combination of iron and essential fatty acids to support their brain development.” (BMS advertisement from Dakar).Most advertisements for specific BMS products (11 out of 16 advertisements in both sites) made nutrition claims and nearly all (13 out of 16 advertisements) made health claims Table . Table 33.2There were four manufacturers whose CPCF were advertised. Two companies advertised products in Phnom Penh and three in Dakar, with one (Nestlé) advertising in both Table .“… contains main nutrients from the 5 food groups for the children's small stomachs.” (CPCF advertisement from Phnom Penh).“… contain essential nutrients included Combifer, a combination of vitamins for his growth and iron to support his brain development”. (CPCF advertisement from Dakar).Of seven advertisements, five (two in Phnom Penh and three in Dakar) indicated the recommended age of use of 6+ months verbally or visually in the advertisement. The number 6 was shown on one product label but no other information (such as the term “months”) was legible. One product label (Babybio) did not show any numbers or ages. Three advertisements had nutrition claims and four had health claims Table . ContentNine of the 11 advertisements for BMS products and two out of the three CPCF advertisements in Phnom Penh displayed a text‐based message indicating approval from the Ministry of Health/Ministry of Information.See 3.3During the 13‐month period monitored, the average monthly cost of advertising for brands/products on television for BMS in Phnom Penh was estimated at US$46,760 per month. CPCF were only advertised during the first 4 months of the monitoring period; the average cost was US$6,474 per month during these 4 months. Costs could not be calculated in Dakar because costs were distributed throughout numerous countries that received the advertising from France and Cameroon, not just Senegal.4This study assessed television advertising of BMS and CPCF in Phnom Penh, Cambodia, and Dakar, Senegal. BMS products were advertised in both sites, despite clear prohibition of such promotion in the International Code of Marketing of Breast‐milk Substitutes. Both Cambodia and Senegal have legal measures in place to enforce the International Code of Marketing of Breast‐milk Substitutes, but neither has adopted all provisions into law ” .” It is essential that products clearly state the suggested earliest age of use and that this should not be less than 6 months for some BMS and all CPCF. In addition, countries should introduce and enforce policies regulating appropriate marketing of CPCF, including clear indication of the appropriate age of introduction. Manufacturers and distributors of products for infant and young child feeding must ensure that they are meeting their responsibilities under The International Code of Marketing of Breast‐milk Substitutes and subsequent WHA resolutions including WHA 69.9. More clarity is needed from global regulatory bodies with regard to nutrition and health claims on foods for infants and young children.The authors declare that they have no conflicts of interest.SH and EZ conceptualized and designed the study. HK and AP oversaw data collection and write up of initial results in Phnom Penh, whereas EID and NYSG did so in Dakar. SH and MC drafted the manuscript. JB guided the nutrition and health claims analysis. All authors reviewed and contributed to the final manuscript.BMSBreast milk substituteCPCFCommercially produced complementary foodUSUnited StatesWHAWorld Health AssemblyWHOWorld Health OrganizationData S1. Supporting informationClick here for additional data file.


Only one‐third of young people who experience suicidal ideation attempt suicide. It is important to identify factors which differentiate those who attempt suicide from those who experience suicidal ideation but do not act on these thoughts.ALSPAC), a UK population‐based birth cohort. Suicide ideation and attempts were assessed at age 16 years via self‐report questionnaire. Multinomial regression was used to examine associations between factors that differentiated adolescents in three groups: no suicidal ideation or attempts, suicidal ideation only and suicide attempts. Analyses were conducted on an imputed data set based on those with complete outcome data  at age 16 years .Participants were 4,772 members of the Avon Longitudinal Study of Parents and Children . They were also more likely to have a psychiatric disorder . Other risk factors included female gender, lower IQ, higher impulsivity, higher intensity seeking, lower conscientiousness, a greater number of life events, body dissatisfaction, hopelessness, smoking and illicit drug use (excluding cannabis).The lifetime prevalence of suicidal ideation and attempts in the sample was 9.6% and 6.8% respectively. Compared to adolescents who had experienced suicidal ideation, those who attempted suicide were more likely to report exposure to self‐harm in others (adjusted The extent of exposure to self‐harm in others and the presence of psychiatric disorder most clearly differentiate adolescents who attempt suicide from those who only experience suicidal ideation. Further longitudinal research is needed to explore whether these risk factors predict progression from suicidal ideation to attempts over time. 10.1111/jcpp.12982Read the Commentary on this article at doi:  Thoughts of suicide  are common in adolescents and are a well‐established risk factor for suicidal behaviour   is a key determinant in each of the three models. Factors thought to be related to this concept include increased fearlessness about death; persistence through pain and distress; exposure to self‐harm in others; knowledge about and access to lethal means; and previous non‐suicidal self‐harm. A recent review of the literature found factors related to increased suicide capability were consistently associated with suicide attempts amongst those with ideation  explore risk factors for adolescent suicidal ideation and attempts and (b) identify factors that distinguish between these groups. We compared a wide range of recognised risk factors between three groups: those who had attempted suicide, those who had thought about suicide but never made an attempt and those without any suicide history. Our analyses were exploratory, given the limited research in this area. However, as suicide capability is a key component of the theoretical models of suicide, we hypothesised that putative risk factors related to increased suicide capability (such as exposure to self‐harm in others) would most clearly differentiate between those with a history of ideation and those who had attempted suicide.http://www.bristol.ac.uk/alspac), which includes details of all available data via a fully searchable data dictionary . Ethical approval for the study was obtained from the ALSPAC Law and Ethics committee. Written informed consent was obtained after the procedure(s) had been fully explained.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a population‐based birth cohort study examining influences on health and development across the life course. The ALSPAC core enrolled sample consists of 14,541 pregnant women resident in the former county of Avon in South West England (United Kingdom), with expected delivery dates between 1 April 1991 and 31 December 1992  study . These included sensation seeking; exposure to self‐harm in friends and family; life events; and hopelessness. Risk factors collected prior to the age 16‐year assessment included gender; IQ; executive function; impulsivity; personality dimensions; parent suicide attempt; sexual abuse; parental cruelty; being bullied; body dissatisfaction; psychiatric disorder; depression symptoms; heavy drinking; cannabis use; and illicit drug use (excluding cannabis).Additional analyses controlled for the possible confounding effects of child gender and socioeconomic position (SEP). We did not adjust for additional confounders, as our aim was to identify potential differences in risk factors for suicidal thoughts and attempts rather than to build the most parsimonious prediction model.Socioeconomic position was assessed via maternal questionnaire and included (a) average weekly household disposable income recorded at age 3 and 4 years, divided into quintiles and rescaled to account for family size, composition and estimated housing benefits . Continuous risk factors were standardised before analysis to create Z scores with a mean of 0 and a SD of 1. We explored the possibility of nonlinearity by dividing continuous risk factors into quintiles and testing whether a categorical variable was a better fit to the data using the likelihood ratio test. Extraversion showed evidence of a ‘J‐shape’ relationship, and so this variable was split into three categories prior to analysis . All analyses were conducted using Stata version 14.Multinomial regression was used to examine associations between each individual risk factor and a three‐category outcome: no suicidal ideation or attempts, suicidal ideation only and suicide attempts. Models were adjusted for sex and SEP. To obtain a direct comparison between suicidal ideation and attempts, each model was re‐estimated with an alternative reference group to provide this additional information. A risk factor was considered to be associated with an outcome if the confidence interval did not include the null   reported no suicidal ideation or attempts, 456 (9.6%) reported suicidal ideation only and 325 (6.8%) reported a suicide attempt. Descriptive information on risk factors according to outcome group is provided in Table N = 4,772). The ORs in Table Findings from the multinomial logistic regression analyses are shown in Table The results for each risk factor are shown in Table This study investigated factors distinguishing between adolescents who had thought about suicide and those who had made an attempt. Over half of the risk factors we considered distinguished between those with ideation and attempts, however, many had small effects. Notably larger effect sizes were found for exposure to self‐harm in family/friends, mental health disorders and also smoking and illicit drug use (excluding cannabis).Recent theoretical models all emphasise the role of ‘suicide capability’ in the progression from suicidal ideation to attempts . In contrast, heavy drinking and cannabis use did not differ across these groups, highlighting the importance of examining substances individually. Alcohol is the substance that has been researched most widely in the literature, as it is thought that its intoxicating effects may increase aggression, impair decision‐making and lower inhibition, making it more likely that someone will act on suicidal thoughts. However, most previous studies, including a recent meta‐analysis of adults, have not found alcohol problems to be elevated amongst attempters compared to ideators  reverse causation is possible. We found that associations tended to be stronger for those variables measured more proximally to the outcome , although this was not always the case . Moreover, for some variables , the timing of assessment would have little or no impact on the results, as these variables are fairly stable or fixed over time. As the study involved secondary analysis of an existing data set, the selection of measures was dependent on data availability, and we were not able to test hypotheses regarding the timing of exposure, or whether the findings would differ according to developmental stage.Third, we only adjusted for a limited number of confounding variables (gender and SEP) and it is possible that there may be residual confounding. However, it was not our aim to identify independent predictors and to examine this adequately would require a separate theory‐driven analytical model for each exposure. This was beyond the scope of the current paper but is an important area for future research. We did not correct for multiple testing as analyses were exploratory, and a number of risk factors are likely highly correlated. Our results are therefore in need of replication, given the large number of tests conducted.N = 4,772). Our imputation analysis assumes follow‐up depends only on those individual characteristics observed and included in the imputation model . It is likely that the risk factors involved in progression from ideation to attempts may vary across the life course. This possibility should be investigated in future research.. Our results also highlight the continued importance of identifying and treating mental health problems, as they are strongly associated with the development of suicidal ideation and likely have a role in progression from thoughts to behaviour. It is also important for suicide prevention efforts to consider disorders other than depression. Future research should build on these findings and prospectively follow‐up those with suicidal ideation, to explore whether the factors identified in this study predict subsequent suicide risk.The results of this study have important implications for both clinical practice and suicide theory. Identifying factors that differentiate between those with suicidal ideation and attempts can help to improve risk assessment  and identify potential targets for intervention. Our findings suggest that youths who make suicide attempts are likely to have had exposure to self‐harm in others, underscoring the importance of practitioners considering the social context in which suicide attempts occur and the possibility of modelling, contagion and environmental reinforces of self‐harm behaviourA third of young people who experience suicidal ideation attempt suicide. However, little is known about the factors that differentiate those most likely to attempt suicide from those who only think about suicide.We examined this issue in a population‐based sample of over 4,700 adolescents.The factors that most clearly differentiated between those with a history of suicidal ideation and attempts were exposure to self‐harm in friends/family and psychiatric disorder.Prospective studies are needed to explore whether these risk factors predict future suicide attempts.Table S1. Comparison of responders and non‐responders to the self‐harm questionnaire at 16 years by key demographic variables.Table S2. Descriptive table for risk factors.Table S3. Multinomial logit model investigating associations between risk factors and adolescent suicidal thoughts and attempts.Table S4a. Comparison of complete case and imputed analysis.Table S4b. Comparison of complete case and imputed analysis.Appendix S1. Missing data.Click here for additional data file.


For diagnosing glioma, this approach has unfortunately proven to be of limited use since glioma contribute minimal ctDNA to the blood circulation. A more promising avenue may therefore be to hunt for ctDNA in cerebrospinal fluid (CSF). The study by Mouliere  Each year, more than 200,000 individuals are diagnosed with glioma worldwide  in the blood circulation have shown exciting promise . The presence of tumor DNA in CSF was first reported in 1995 by Harker Rhodes l, et al  used botl  in CSF‐sWGS data. SCNAs were detected in the CSF of five out of 13 glioma patients as focal events confined to individual genes and as large events spanning entire chromosomes. Similar SCNAs were not seen identified in matched plasma samples, confirming earlier reports that cfDNA in CSF better represents the genomic alterations of brain tumors than cfDNA in plasma (Bettegowda et al, To study structural features in CSF‐cfDNA on molecular scales, the authors implemented paired‐end DNA sequencing, which provides sequence information from both ends of the molecules, and obtained the size distribution of cfDNA fragments in CSF. This analysis revealed a shortening of fragments in the CSF of patients with primary brain tumors. A similar shortening has been observed for ctDNA in plasma (Underhill et al,et al,et al,et al is an important early step in the creation of diagnostic protocols that take advantage of low‐cost screening via CSF‐cfDNA to identify samples where more expensive, confirmatory testing is needed. First however, further study is necessary to validate the concepts put forward in this paper in a larger cohort of patients.Cell‐free DNA in CSF provides a compelling, information‐rich window into the genetic makeup and biology of brain cancers (Harker Rhodes The authors declare that they have no conflict of interest.


Anaphylaxis is a life threatening systemic inflammatory process that share mediators involved in the coagulation cascade. Platelet activating factor, known to increase platelet aggregation, has also been implicated as an important mediator of anaphylaxis. Although other inflammatory reactions are associated with an increased risk of thrombosis, anaphylaxis is currently not reported as one of them. Furthermore the role platelets may have in the perianaphylaxis period is not well understood. We here in present a retrospective case series of three patients that had platelet aberrations suggestive of PAF involvement and clinically significant thrombosis in close relationship with anaphylaxis.To investigate platelet response before and after anaphylaxis and indirect observation evidence of platelet activating factors involvement with possible increased risk of thrombosis.A retrospective investigation into medical records including medication administrations times, laboratory, and radiology results. Platelet levels pre‐ and post‐ anaphylaxis were statistically analyzed.P < 0.0001.Case 1, a 44 year old man had an anaphylactic reaction shortly after envenomation and subsequently suffered an acute infarction with thrombus in a cerebral artery. Case 2 is a 49 year old man with idiopathic anaphylaxis who developed a deep vein thrombosis after a protracted anaphylaxis event. Case 3 involved an 18 year old female with acute myeloid leukemia was found to have a thrombus in the celiac trunk following anaphylaxis. A paired two‐tailed Wilcoxon test on the subjects pre and post anaphylactic platelet levels resulted in a overall These three cases illustrate the potential role platelets may have in anaphylaxis and possible increased secondary risk for the development of thrombosis. Larger studies are required to determine incidence and risk factors for blood clots following anaphylaxis in order to provide management or screening recommendations. Anaphylactic reactions are life threatening systemic inflammatory processes that share some mediators which are also involved in the coagulation cascade pathways. Platelet activating factor (PAF), known to increase platelet aggregation, has been implicated as an important mediator of anaphylaxis This study was approved by University Hospitals Cleveland Medical Centers Institutional Review Board, approval number NHR‐16‐109. Patient histories, clinical event notes, laboratory and radiology results, and medication administrations times were investigated and cross referenced. GraphPad Prism 7 with confidence level of 95% was used for all statistical analysis. A paired two tailed Wilcoxon test was performed on the pre and post platelet levels due to the nonparametric distribution of the platelet levels among the three participants in the case series. A Spearman test was used on the pairing. A Kruskal‐Wallis test was performed on Case 3's platelet levels with respect to the frequency of pentamidine infusions and off pentamidine. Platelet counts are listed as “Pre‐” if they were taken the day before or earlier in the day before an attack. Platelet counts listed as “Post‐” were taken after an anaphylactic attack and were at least within 24 h of the event. Case 1 did not have a “Pre‐” platelet level. In this case the platelet level obtained within the 1st hour of the attack and was paired with a 12 h post‐event level. If more than one platelet level was obtained on the day of, but before a clinically identifiable anaphylactic attack they were matched with the platelet level of the closest circadian time frame of the following day.This case was previously published and will only be reviewed briefly here The patient is a 49 year old man with psoriasis and idiopathic anaphylaxis—generalized frequent type The events leading to his DVT started weeks prior when he experienced urticaria and angioedema of his face, body, and extremities without association of additional systemic symptoms. The urticaria and angioedema was initially responsive to steroids and antihistamine treatment, but within weeks became refractory and progressive. A subsequent sudden episode of respiratory distress with hypoxia resulted in an emergent crico‐thyroidotomy.During his hospitalization subject 2 had recurrent anaphylaxis. Multiple physicians reported bilateral wheezing and poor air exchange during respiratory distress episodes. The events were unresponsive to tracheotomy hygiene and albuterol, but resolved after IM epinephrine. One incident required an epinephrine drip for 12 h. Within 24 h of an anaphylaxis episode he developed an acute occlusive left upper extremity DVT. He has had a total of four hospital admission within 1 year for anaphylaxis. During his third admission he developed an acute worsening of his chronic left upper arm DVT. With each anaphylactic attack a drop in his platelet levels were seen  was found to be allergic to her pentamidine treatments. She developed nonocclusive thrombus involving the celiac trunk, proximal hepatic, and splenic arteries shorty after her first pentamidine administration. She originally started intravenous (IV) pentamidine after developing a nonspecific rash  initially attributed to trimethoprim/sulfamethoxazole.Twenty minutes into her first administration of IV pentamidine she developed severe crippling abdominal pain, emesis, diarrhea, and light headiness followed by near‐syncope. Abdominal X‐ray showed non‐obstructive gas patterns with small bowel wall thickening. After resolution of her abdominal pain she was given a platelet transfusion for thrombocytopenia Table . During An abdominal CT scan showed colonic wall thickening with surrounding inflammatory changes and concern for ischemic colitis. An MR enterography revealed a nonocclusive thrombus involving the celiac trunk, proximal hepatic, and splenic arteries. The patient underwent a partial colectomy from the mid transverse colon to mid distal colon. The pathology results showed patchy transmural ischemic colitis without evidence of local thrombosis or emboli. Continued treatments of IV pentamidine every 2 weeks were noted to have immediate production of a range of symptoms mostly commonly: abdominal pain, emesis, pruritus , diarrhea and headaches. Pentamidine allergy was established and desensitization protocol was subsequently used. Isolated urticarial flares with each desensitization was reported without any other clinical systemic involvement.P < 0.0001 was restarted. Her thrombocytopenia again incrementally improved to the 80–100's. A Kruskal‐Wallis test on her platelet levels with respect to the frequency of her pentamidine infusions and off pentamidine showed a 1 Figure .The coagulation cascade share many for the same inflammatory mediators with processes such as: sepsis, shock, asthma, allergies, and anaphylaxis. To date all of these medical ailments except for anaphylaxis is listed as being associated with increased risk of thrombosis and blood clot formation In this case series all three subjects differ greatly in the trigger of the anaphylaxis along with their respective baseline coagulation risk factors. Irrespective of the trigger or clotting risk factors, all patients suffered clinically significant thrombosis within 72 h of an anaphylactic event. For each subject this was the first occurrence of a thrombosis or blood clots in their lives. This makes the timing of the events more meaningful with simple coincidence less likely. Two of the three cases had no signs of shock during their anaphylaxis.The association of allergies with the formation of venous thromboembolism has been explored in several studies to include: asthma, allergic rhinitis, atopic dermatitis, and increased IgE levels Case 1 had a classical IgE‐mediated anaphylactic event following venom injection by a stinging insect. Studies have already shown that venoms can trigger a decrease in factor V, VIII, and fibrinogen leading to a prothrombotic environment Case 2 suffered from a malignant form of idiopathic anaphylaxis—generalized frequent type Subject 3's allergic reaction to pentamidine is not clear whether her reaction was truly IgE‐mediated anaphylaxis or anaphylactoid, with the latter being favored. The spacing out of her pentamidine infusions showed modest increases in her baseline platelet levels. Once pentamidine was stopped there was an almost doubling of her previous platelet counts after 8 weeks. The exact cause of her apparent persistent mild baseline thrombocytopenia (100 to <150) is unknown. It is however reasonable given her ANOVA results on her infusion frequency and off pentamidine, that her allergy to pentamidine may have compounded her thrombocytopenia. A low level of persistent PAF stimulation, given the absence of specific antibodies to platelets on work‐up, could account for the compounded thombocyctopenia Studies on PAF levels and platelet activating factor acetylhydrolase (PAF‐AH) enzyme responsible for the metabolism of PAF has been reported to correlate with the severity of an anaphylactic event P < 0.0001.Transient sequestering and aggregation of platelets in the lungs and liver secondary to PAF has been reported in laboratory experiments with rabbits and other animals Heparin‐induced anaphylaxis and thrombocytopenia has been reported It is well known that anaphylaxis and other inflammatory processes share common mediators with the coagulation cascade. These 3 cases illustrate the potential role platelets may play during and after IgE‐mediated anaphylaxis and non‐IgE anaphylactoid reactions in humans. Investigations into the platelets aberrations in response to and overall risk factors for blood clots following anaphylaxis are needed in order to provide conclusive recommendations. Although, the above data suggests a cautionary approach in these situations.This study was approved by University Hospitals Cleveland Medical Centers Institutional Review Board as non‐human research (NHR), approval number NHR‐16‐109. A waiver of consent, ethical permission, was granted secondary to the retrospective nature of this NHR study.There are no conflicts of interest to report by any of the authors.