Ciliated multinodular papilloma tumor (CMPT), a subtype of proximal bronchiolar adenoma (BA), is a rare mucin‐producing papillary tumor arising in the peripheral lung. The nature of CMPT is so far controversial. The hypothesis that CMPT is a precancerous lesion that can lead to mucinous adenocarcinoma requires further research. A 61‐year‐old man with a ground‐glass opacity (GGO) suspected to be lung adenocarcinoma in the right lower lobe of his lung underwent surgical treatment. Postoperative pathology suggested that the patient had mucinous adenocarcinoma caused by cancerization from CMPT. Targeted next‐generation sequencing (NGS) was utilized to detect driver mutations in tumor DNA. Among the identified mutated genes, there were regrettably no high frequency mutations. This report describes a case of mucinous adenocarcinoma caused by cancerization from CMPT, indicating that CMPT may be a neoplasm rather than a metaplastic process and provides histological evidence for the hypothesis that CMPT is a precancerous lesion of mucinous adenocarcinoma. This report describes a case of mucinous adenocarcinoma caused by cancerization from CMPT. This indicates CMPT may be a neoplasm rather than a metaplastic process and provides histological evidence for the hypothesis that CMPT is a precancerous lesion of mucinous adenocarcinoma Ciliated multinodular papilloma tumor (CMPT) arises in the peripheral lung fields and is associated with the proliferation of ciliated and goblet cells and increased mucin production. CMPT was first reported by Ishikawa and Tsuchiya in 2002A 61‐year‐old man with a smoking index of 100 was admitted to our department for evaluation of a 14 mm ground‐glass opacity (GGO) in the right lower lobe of his lung, which had been an incidental finding six months previously . Macroscopic examination of the resected lung parenchyma specimen showed a well circumscribed gray nodule measuring 10 × 18 × 15 mm. Pathology and hematoxylin & eosin (HE) staining showed that there was a double‐layer cell structure composed of basal and ciliated cells, which were typical of CMPT, but the basal cells in some areas were discontinuous or even disappeared, which was one of the reasons why we suspected cancerization Figure . ConfirmTo explore the underlying molecular mechanisms and their potential therapeutic relevance, we utilized targeted next‐generation sequencing (NGS) to detect driver mutations in tumor DNA (tDNA) . A panel of 825 tumor‐related genes was subjected to NGS. The sequencing results identified 18 genes that each contained a single missense mutation  and confirmed the concept that CMPT is a neoplastic disease as opposed to a reactive or metaplastic lesion.EGFR, BRAF, ALK and KRAS), which supports the notion that the lesions tend to be neoplastic with malignant potential. Therefore, CMPT may be classified as a low‐grade malignant tumor. Although partial resection or segmentectomy might be sufficient for these low‐grade malignant or borderline tumors, pre‐ and intraoperative diagnosis is difficult and standard lobectomy remains the treatment of choice.The nature of CMPT is so far still controversial. Recent genetic studies have revealed mutations in some driver oncogenes (EGFR, KRAS or other known candidate genes involved in lung tumorigenesis, at least during the initial stages. In this case, there were some rare mutations found on next‐generation sequencing the tissue. The mutation distribution from TCGA of genes associated with lung cancer in the case reported here are highlighted in Figure Based on the limited data currently available, some studies have suggested that CMPT is the precursor of mucinous adenocarcinoma, analogous to the established AAH‐AIS‐adenocarcinoma sequence.In conclusion, we report a right lung lower lobe GGO that was found in this patient on CT and diagnosed as mucinous adenocarcinoma caused by cancerization from CMPT. The case provides histological evidence for this hypothesis that CMPT can be the precursor of mucinous adenocarcinoma. More cases and further studies are also needed to confirm the genetic and histological nature of CMPT.All authors have declared no conflicts of interest.


This important feature of oncolytic viruses can result in the warming up of immunologically ‘cold’ tumour types, presenting the enticing possibility that oncolytic virus treatment combined with immunotherapies may enhance efficacy. In this review, we assess some of the most promising candidates that might be used for oncolytic virotherapy: immunotherapy combinations. We assess their potential as separate agents or as agents combined into a single therapy, where the immunotherapy is encoded within the genome of the oncolytic virus. The development of such advanced agents will require increasingly sophisticated model systems for their preclinical assessment and evaluation. In vivo rodent model systems are fraught with limitations in this regard. Oncolytic viruses replicate selectively within human cells and therefore require human xenografts in immune‐deficient mice for their evaluation. However, the use of immune‐deficient rodent models hinders the ability to study immune responses against any immunomodulatory transgenes engineered within the viral genome and expressed within the tumour microenvironment. There has therefore been a shift towards the use of more sophisticated ex vivo patient‐derived model systems based on organoids and explant co‐cultures with immune cells, which may be more predictive of efficacy than contrived and artificial animal models. We review the best of those model systems here.Oncolytic viruses possess the ability to infect, replicate and lyse malignantly transformed tumour cells. This oncolytic activity amplifies the therapeutic advantage and induces a form of immunogenic cell death, characterized by increased CD8 Oncolytic virotherapies have immense potential to ‘heat up’ otherwise immunologically ‘cold’ tumour types. In this review, the capacity of virotherapies to synergize with or express a range of types of immunotherapies is explored. Optimizing such combinations in preclinical models is complex, and we therefore review the most clinically relevant rodent and ex vivo human models available for such assessment.  BiKEBispecific NK cell engagersBiTEBispecific T‐cell engagingCAFcancer‐associated fibroblastCARchimeric antigen receptorcBITEEGFR‐targeting BITECEAcarcinoembryonic antigenCTLA4cytotoxic T‐lymphocyte‐associated protein 4DNAdeoxyribonucleic acidEGFRepidermal growth factor receptorEMAEuropean Medicines AgencyEnAdenadenotucirevEpCAMepithelial cell adhesion moleculeFAPfibroblast‐activating proteinFDAFood and Drug AdministrationGM‐CSFgranulocyte‐macrophage colony‐stimulating factorGSCglioblastoma stem cellHER2human epidermal growth factor receptor 2HSCshaematopoietic stem cellsICIimmune checkpoint inhibitorIL‐2interleukin‐2IL‐12interleukin‐12IL‐15interleukin‐15ImmTACsimmune mobilizing monoclonal T‐cell receptors against cancermAbmonoclonal antibodyMHCmajor histocompatibility complexNDVNewcastle disease virusNKnatural killerOVoncolytic virusPD‐1programmed cell death protein 1PDEpatient‐derived explantPDXpatient‐derived xenograftpHLAhuman leucocyte antigen peptideRNAribonucleic acidScFvsingle‐chain variable fragmentTAAtumour‐associated antigenTCRt‐cell receptorTMEtumour microenvironmentTregT regulatoryT‐VECtalimogene laherparepvecVDEPTvirus‐directed enzyme prodrug therapyWhilst it is clear the immune system can recognize and kill cancer cells, it is evident that for the most part that cancers have evolved many mechanisms for evading immune attack. Whilst current immunotherapies, such as checkpoint inhibitors and cellular therapies, can overturn or overcome these mechanisms, they are only successful in certain types of cancer and only in a minority of patients. There is, however, tremendous scope for improvement through a better understanding of the barriers to immune attack and development of novel methods for stimulating effective anti‐cancer immune responses. As discussed below, oncolytic viruses are poised to offer answers to both challenges in that they can be engineered to specifically infect cancer cells whilst simultaneously delivering immune‐enhancing therapies selectively at the site of infection.The use of oncolytic viruses (OVs) as anti‐cancer therapeutics offers potential to break tumour tolerance. Although some viruses have naturally improved ability to replicate within cancer cells, most OVs are engineered agents that have been refined to selectively infect or replicate within transformed cells. A wide range of OVs are under development, with those based on adenovirus, herpes simplex virus, reovirus, vaccinia virus, measles virus, Coxsackie virus and Newcastle disease virus (NDV) proving effective at the preclinical level, with some progressing to clinical trials , 2, 3. An additional appealing feature of oncolytic viruses is the capacity of the viral genome to encode therapeutic transgenes. Early studies focussed on transgenes that were indirectly toxic to tumour cells, in particular the use of ‘virus‐directed enzyme prodrug therapy’ (VDEPT). A notable example of this is nitroreductase , which cThe immunogenic nature of cell death induced by an OV has significant promise in sensitizing tumours to immunotherapies , 12, 17.Until recently, the mainstay cancer treatments were limited to combinations of chemo‐radiotherapy, surgery and targeted therapies. Although advances in each of these treatments have sought to minimize side‐effects, these remain a significant issue . It has +ICOS+ T cells were associated with significantly improved therapeutic outcomes. At the time of writing, a phase 3 clinical trial studying the combination of pembrolizumab (anti‐PD‐1) with and without T‐Vec has just completed, the results of which are eagerly anticipated (NCT02263508). These studies demonstrate the significant potential to combine the self‐amplifying ability of virotherapies with the local tumour selectivity of immunotherapies to enhance anti‐tumour immune responses. The potential synergy of OVs with ICIs has made their combination use in clinical trials popular, and a wide range of combinations are currently being assessed . Wi. Wi56]. sive TME , 58.To increase the effectiveness of the anti‐tumour activity of CAR T cells, a combination of OVs and BiTEs has been utilized. CAR T cells targeting folate receptor α can successfully infiltrate pre‐established xenograft tumours but failed to induce a complete response due to the presence of antigen‐negative tumour cells . As theyOncolytic viruses can be readily engineered to combine different immunotherapies including BiTEs, cytokine production and ICIs. Porter et al. generateA novel format of bispecific molecules are the immune mobilizing monoclonal TCRs against cancer (ImmTACs) that uses TCR specificity to engage with target cells . BispeciMechanisms of tumour selectivity are virus‐dependent and need to be determined and proven efficient before these treatments enter the clinic to rule out any adverse effects. At the very least, the model system used to evaluate an OV depends on the OV in question, what is being targeted, the condition being treated, the mechanism of action and whether it is being considered as a mono‐ or combination therapy. Thus, selection of appropriate models for testing and validation will need to take each of these considerations into account.A major limitation of OVs is the host‐selective nature of replication, as many of the human‐specific OVs that would be utilized as virotherapies cannot replicate in murine cells and tissues. In order to study off‐target replication toxicity for this virus, only human cells would provide reliable and meaningful results; therefore, a set of preclinical studies using a combination of in vitro safety tests needed to be designed . It is t+ haematopoietic stem cells (HSCs) resulting in successful engraftment of a human immune system and enabling immune responses to PDX to be assessed [Initial validation of OV therapies have been carried out in cell lines to ensure OV is able to specifically replicate in tumour cells or can target certain markers ; howeveassessed . Tsonevaassessed  used sucassessed , 70.As alternatives to the use of mice–patient chimeric system, other derived models such as organoid‐ or patient‐derived explants (PDEs) have been effectively used for the study of OV. PDEs have proven useful as the tumour borders can be cut precisely to include both tumour and healthy tissues, thereby allowing the demonstration that a given OV targets the tumour specifically. Upon infection, it is possible to observe viral transgene expression to prove viral replication and the tissue can be cut and stained for further analysis. Whilst PDEs have been used for OV validation in a variety of settings , their uConsiderable evidence now points towards an additive or even synergistic potential of OVs and immunotherapies, either as a combination therapy or as one ‘Trojan horse’therapy, where the immunotherapy is encoded within the OV genome. There exists a plethora of viral platforms, targeting strategies and immunological payloads that can be combined into highly advanced complex therapies for future clinical translation. Defining suitable models to enable high‐throughput evaluation of these therapeutics and optimize combinations remains a challenge. Combinations of advanced models based on ex vivo evaluation in clinical isolates with increasingly sophisticated in vivo models will be required to define optimized and patient‐personalized therapies moving forward.The authors have no disclosures to make.Table S1Click here for additional data file.


To explore and describe nurses' self‐expression media image during COVID‐19 pandemic in China.Nurses play an important role in COVID‐19 pandemic. Although nurses were widely reported by the media, which included praise for nurses and nursing work, the researches on how nurses expressed their self‐images were limited.Qualitative media analysis.Qualitative media analysis was conducted from January to April 2020, the researchers collected images and texts of 16 Chinese nurses who take care of COVID‐19 patients. These images and texts were published on WeChat Moments by themselves. After analysed each image and text, researchers identified the denotative and connotative elements in each image and summarized each image in narrative way.This study analysed 219 pictures and 15 short videos of 16 nurses' self‐expression in WeChat moments. In this study, the media image self‐expression of nurses were mostly positive. The images expressed by nurses in this study included care image; hero image; soldier image; female image; hope image and team image. Nurses rarely showed negative images in the media; The negative nurses image were expressed in hidden way, which included exhausted nurses image and fragile nurses image. Moreover, the nurse self‐expression media image emphasized the nursing professionalism, but less showed the nursing connotation.The positive media image self‐expression of nurses should be encouraged. Nurse Managers should pay attention to the deficiency of nursing image expression and guide nurses to show the essence and connotation of nursing. The nurse media image self‐expression is a necessary component of the nurse public image. Nursing managers should encourage nurses to establish positive media image on social media and show the complexity and importance of nurses' work. These measures may become windows for the public to understand nurses in public health emergencies and may enhance the public's confidence in the medical system's response to COVID‐19 pandemic.Our study follows Standards for Reporting Qualitative Research (SRQR).1The COVID‐19 pandemic is a great challenge to human health worldwide  What are the nurses' images, which self‐expression during the COVID‐19 pandemic? and how them expressed themselves? (2) What are the reasons for promoting or inhibiting nurses' self‐expression during the COVID‐19 pandemic?22.1The methodological framework used in this study was the Qualitative Media Analysis (QMA)  clear pictures (not included patients’ characteristics) (2) the relevant pictures and texts of nurse's image expression published on WeChat Moments during the COVID‐19 pandemic. Then evaluators interpret the pictures write text materials to describe the connotative and denotative elements of the images, respectively .First, the researchers explained the study purposes to the participants in detail. Only researchers can observe and analyse these photos and texts and the data only be used for research.Secondly, we ensured the security of photos. The researchers ensured texts confidentiality by using the code to blur the identifiable information  and deleted the identification information from the records. Researchers blurred some patients in pictures by special technology .Third, all data were saved on a password‐protected computer. Additionally, following the principle of confidentiality, which can be consulted only by researchers of the study group. All data would be kept for three years after the end of the study and then destroyed.Although the photos and texts about nurses' COVID‐19 care were displayed by themselves at WeChat Moments. However, when the researchers explained that data was used for research purposes, some nurses refused. Finally, 16 nurses agreed to participate in the study.3We recruited 16 nurses from five hospital in Shanxi, China. As the nurses supporting Wuhan in China, they witnessed the whole process about COVID‐19 nursing Discourse power limited the expression of negative information; (2) Participants with negative expression were not included in the study; (3) Special experience evoked professionalism and ignored the expression of negative information; (4) Family and friends' worried about work situation; (5) Fear of negative expression might cause public panic. A study found nursing students were cautious about their Facebook posts. The survey found that for security reasons, 40% of students hesitated "sometimes" before sharing information on Facebook  The media image expression of nurses obtained by objective sampling method in this study may had limitations and could not represent the whole country; (2) There may be bias in the study, individual expression may exaggerate the positive part because of the particularity of discourse power. There is no actual interview to clarify, and further study need to interview nurses and to explore the relationship between media expression and social interaction.6This study revealed the nurses images by themselves provided in WeChat Moments during their took care of COVID‐19 patient in Wuhan, China. Positive nurse images included care image; hero image; soldier image; female image; hope image and team image. Negative nurses image also hided in this study were exhausted nurses image and fragile nurses image. The positive media image self‐expression of nurses should be encouraged. Nurse managers should pay attention to the deficiency of nursing image expression and guide nurses to show the essence and connotation of nursing.There are no conflicts of interest in this study.Huili Cao, Hui Yang, Qiaohong Wang: Made substantial contributions to conception and design; Huili Cao, Yangjie Chen, Xingyue He, Yejun Song: Acquisition of data or analysis and interpretation of data; Huili Cao, Hui Yang, Qiaohong Wang: Involved in drafting the manuscript or revising it critically for important intellectual content; Huili Cao, Hui Yang, Qiaohong Wang, Yangjie Chen, Xingyue He, Yejun Song: Given final approval for the version to be published. Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated.Our study was approved by the ethical committee of The First Hospital of Shanxi Medical University .


This article analyzes City of Cambridge, Massachusetts legislation that requires all gasoline and diesel pumps to display a consumer warning label outlining the climate change and public health impacts from fuel combustion. This review of empirical and theoretical scholarship on efficacy of carbon label programs and health warning labels suggests government‐sponsored “warming labels” may increase self‐efficacy beliefs. The analysis reveals warming labels may activate extant climate concern norms and shift public opinion toward long term support of sustainable transportation emissions policies and practices. This review of empirical and theoretical scholarship on efficacy of carbon label programs and health warning labels suggests government‐sponsored “warming labels” may increase self‐efficacy beliefs. The analysis reveals warming labels may activate extant climate concern norms and shift public opinion toward long term support of sustainable transportation emissions policies and practices. Where participation and commitment of citizens can pave the way for its immediate and long‐term successful implementation.1 Prod Cambridge, MA, and North Vancouver, BC place a consumer climate change‐public health warning label or “warming labels” on all transportation fuel pumps. These labels indicate that continuing to burn fossil fuels is a moral liability from human actions. Although labels may not radically shift consumer behavior, they can improve an audiences’ ability to make choices and alter preferences. This, in turn could promote climate policies and actions to reverse unacceptable practices creating harms for human health and well‐being.Nascent government initiatives in Sweden,4 Camb Private voluntary labels can generate emissions reduction through choosing lower carbon options in purchasing decisions. Sweden is an example of a public standard carbon label on a gas pump promoting lower carbon options. Sweden will use a graded scale of greenhouse gas intensity, that is, labels display a “climate impact” rating system for conventional fuels, biofuel, and EV charging stations, along with the renewable share and raw materials of the fuel. Sweden's eco‐labels utilize preference for lower carbon fuels (and energy sources) designed to nudge consumers toward less carbon‐intense energy sources. North Vancouver, BC is an example of a “hybrid” public standard carbon label initiated by government but controlled and disseminated by the Canadian Fuels Association. Ambiguously promoting private interest, this “Smart Fuelling” program is an example of oil interest intentionally decorating themselves as environmental protectors—which can distort the market for carbon label programs.Warming labels schemes can be initiated by a local government or private agency. A public standard carbon label is where government sets the standards and monitors the program, while a private voluntary standard is owned and operated by a private company.8 PrivWe review scholarship on how exposure to a public health warning label on a gas pump, focusing on the City of Cambridge, Massachusetts measure may shift climate change perceptions, beliefs, attitudes, behaviors, and policy support. The Cambridge public standard scheme will place a bright yellow, text‐only warming label on the front‐center‐face of a gas pump, stating “Burning Gasoline, Diesel, and Ethanol has major consequences on human health and on the environment including contributing to climate change.” The message by city government is an attempt to regulate petroleum‐based transportation fuels as a public health and environmental menace. The message reflects constitutional constraints or government “compelled speech” of a private company. Government‐sponsored warming labels as trusted, experiential education about combustion harms may effectively address the climate knowledge‐action gap. By activating extant climate concern norms , Cambridge warming labels engage the public as crucial actors in enacting and adopting low carbon transport.We highlight the crucial role of domain‐specific communication about anthropogenic climate change in influencing individual and group attitudes toward mitigation.1 GoveWe particularly highlight the relationships between social norms marketing in altering preferences, increasing self‐efficacy beliefs, and shaping the public opinion of autonomous individuals. Based on these findings, we propose directions for future research and best practices for researchers seeking to understand the relationship between warming labels, social norms, and climate action.22.1Labels can act as “guilt” appeals or can be designed to correct misperceptions to motivate climate action. Positive framing in climate messaging however, stimulates action more than negative. At the same time, when someone perceives a  threatening message as significant and personally relevant, that person experiences strong negative emotional responses like fear and worry. Thus, there may be an optimal level of negativity where fear plays an important role in motivating discussions about climate change.As a “guilt appeal,” the Cambridge text may generate a strong sense of responsibility, of surveillance, and a warning that punishment could occur that could become in a circular fashion, a norm itself.10 Pos Self‐efficacy belief is a perceived ability to perform a recommended response, and the perceived effectiveness of the recommended response to avoid the threat determines whether the response to the threatening message is adaptive  or maladaptive . A primary measurement of warming label effectiveness may be the degree to which warming labels increase self‐efficacy beliefs.Warming labels may increase self‐efficacy beliefs when the messaging feels personally relevant so that individuals feel uniquely called upon  to reduce the harms through their own actions.12 Sel As such, they are a social marketing scheme that may correct for pluralistic ignorance. Pluralistic ignorance is a tendency to misjudge what the beliefs and actions of others actually are. Americans currently underestimate the political consensus on climate change . On policy attitudes, majorities think government should do more to reduce the effects of climate change, including regulating carbon dioxide (CO2) as a pollutant. Basic environmental awareness and social responsibility motivation are key to a warming label's ability to motivate greenhouse gas reductions.Warming labels take into account that knowledge is a social process embedded in social practices, identities, norms, conventions, and institutions.13 As  Reminding the public that a majority of Americans share their concern may produce strong  desires to adopt peer group expectations and increase peer‐group pressure in climate change mitigation. Warming labels may promote climate concern norms already present and inform others that a majority share their concern.Warming labels may legitimate everyday interpersonal discussions about climate change where pluralistic ignorance is a barrier to such discussions, which reduces effectively taking collective action.18 Rem2.2 and thus increase the likelihood of their acceptance and practice by decision‐makers. Considering the Cambridge text for example, research found the long residence time of CO2 and negative public health consequences from combustion are poorly understood by most people . The Cambridge text could act like “present risk management tools” reducing uncertainty, complexity, and intangibility to a present here and now where the future must be taken into account.The public interest, educational role of government warming labels about commonly misunderstood, negative effects from combustion may effectively establish trust23 and Trust is a mediating factor in carbon label efficacy, facilitating evaluation of scientific claims about the environment, making information easier to understand that shape public opinion. Trusted warming labels connecting climate‐health harms to individual's routine consumption of fuel could build support for further emissions reductions in transportation.Further, warming labels may indicate how other members of a social group are expected to think and act in specific situations.20 Tru2.3 Brewer et al. and Sampei et al. note trusted climate change information using appropriate timing and context could be powerful across the political spectrum.A trusted source of climate change information for most Americans regardless of political affiliation comes from climate scientists.27 Bre Receiving climate change information through trusted sources would strengthen pro‐environmental stances socially and would give special authority in interpersonal communications; considered the most important in changing attitudes and beliefs.Public interest warming labels utilizing trust in government science is a factor in building self‐efficacy beliefs. According to Rhodes et al. and Perkins et al., trust is significant in achieving implementation of effective emission mitigation policies.29 Rec2.4 They provide the social‐environmental pressure that creates public opinion mainly because individuals find that others think as they do, sanctioning their position. Warming labels may provide a strong normative environment to facilitate the policy changes needed to address climate change by determining who can speak and who cannot, which plays a leading role in public opinion formation.Warming labels may be the only way for a minority  to gauge public opinion and to feel free to express their own in the social environment.32 TheWarming labels may legitimize and anchor minority opinion by lessening the fear alarmed individuals may have about speaking competently or appearing antagonistic when speaking to others about climate change and increasing interpersonal discussions and opinion expression about climate change.342.5 The strength of this not‐alarmed majority in the social environment has the power to punish or sanction minority opinion.An “alarmed” minority (26%) of Americans are fully engaged in and addressing the reality and seriousness of climate change personally and politically—in contrast to a political majority “concerned” but yet not engaged.15 The Warming labels could utilize the role media has as agent of the environmental socialization process. Media messages, such as warming labels that broadly increase the salience of climate urgency, could liberate its importance in dominant public opinion.Media is crucial in focusing attention and constructing behavioral possibilities while limiting counter arguments or evidence.36 War2.6 Alternative climate science communication efforts would not depend on individuals seeking climate change information out of an already held concern but would occur consistently in their everyday lives.Climate change information tends to reach already concerned audiences, with acceptance of climate science occurring along a liberal/conservative continuum that do not reach broader audiences .39 Alt Further, “psyche‐wise” messages about climate change and health can counteract a tendency for individuals to think their individual efforts are insignificant and won't exert an effort unless others do.Trusted warming label's point of sale  location would reach all petroleum fuel consumers. Domain‐specific communication signaling a collective action happening now would end the practice of traditional climate change communication tending to address individuals as isolated actors while not changing the meaning and materials associated with social practices as a more effective way to increase self‐efficacy beliefs.38 Fur Such messaging can facilitate understanding of the cause and effect of man‐made climate change as perpetrated by and negatively affecting us, here and now.Cambridge labels at the pump use an experiential learning approach to climate change communication, emphasizing where learning happens through firsthand, rather than others’ experience.41 Suc However, private‐voluntary carbon labels for consumers with higher ecological values, significantly affected their willingness to purchase low carbon products when acceptability, credibility, and understanding of the labels was relatively high. Onozaka et al. study on private‐voluntary eco‐labels on locally grown fresh apples for example, found labels with both a where‐grown designation and information on the amount of greenhouse gases emitted from the production and distribution of the product, shifted both supply and demand toward local apple production—reducing carbon emissions 7% during the local production season. Similar, Hagman et al. found social norms marketing interventions correct for pluralistic ignorance in sustained ways on campus alcohol use perceptions where most college students overestimate the amount of alcohol their fellow students consume .Public standard carbon labels are more trusted than private‐voluntary standard labels.8 Howe2.7 Forced consumer exposure to warming labels could be informal sources of climate science education, linking general audiences directly to these harms at the time and place of use, and are an experience‐based opportunity to teach that could increase risk perception attitudes or a belief one is vulnerable to impacts from climate change.Both studies illuminate how first‐hand learning via experiential communication can leverage the trustworthiness of the information source to educate the public.41 For are first‐hand learning how immediate harms are generated through one's own actions that may produce self‐efficacy beliefs. Under these conditions, warming labels as domain‐specific, science communication could have a powerful unsolicited effect as they play a complementary role in reporting “everyday” acceptable opinion. Experiential processing is more powerful than analytical processing in driving decision‐making and behavior and stimulating interpersonal discussions. Therefore, warming labels could have a powerful influence on individual decisions about risk associated with increased levels of saliency and risk perception attitudes.Warming labels as physically and psychologically close experiences of climate change42 are2.8 Further, their evaluation supported the effectiveness of experiential learning about climate science. Exposure to informal, experienced‐based climate change education—helping viewers understand the causes, processes, and impacts of climate change—reduced the subject from something remote, complex, and confusing to something proximate, concrete, and trustworthy.Experiential learning at the pump about previously unknown climate‐public health harms is similar to learning about how local weather is affected by man‐made climate change. Zhao et al. found respondents who learn about these effects first‐hand through local TV meteorologists were more certain climate change was happening, understood climate change is primarily human‐caused, and perceived greater harm from climate change.41 FurWith health warning labels (HWLs), negative messaging may be more effective, possibly due to fear‐based messages producing adaptive, desired responses when both a perceived threat (negative perceptions of graphic HWLs on cigarettes) is high and efficacy  is high.11 However, a review of text‐only alcohol HWLs found them to be ineffective. This may be due to tobacco warning labels implemented in the context of intense and persistent public health campaigns against tobacco smoking where the cultural position and politics of tobacco and alcohol differ. On the other hand, an experimental laboratory study where participants viewed HWLs (moderately severe and highly severe) on large beer cans found highly severe HWLs increased an individual's self‐efficacy beliefs; perceiving them as more effective and increasing motivation to drink less.A 2012 longitudinal study in Canada and Australia found graphic imagery HWLs on 75% of the front of cigarette packs promoted cessation behavior; this was predicted by a stronger threat response to graphic HWLs producing stronger self‐efficacy belief .11 How The greater self‐efficacy to quit smoking for instance, is independently associated with stronger threat responses to graphic HWLs on cigarette packs, but not with rejection of their strong emotional messaging.Strong self‐efficacy beliefs to quit smoking or drinking may be linked to climate concern norms where warming labels could conjure a high threat response. Too much or too little arousal in such interventions can hinder the climate action performance. At the same time, climate change beliefs and expectations about future conditions are shaped by the physical and social world.1 The The obvious differences in efficacy between highly severe graphic HWLs and text‐only messages notwithstanding, the (above) results suggest an optimal level of negativity in warming label messaging interacting with an already socially salient climate concern. And perhaps the need for multi‐media campaigns that support warming label programs. Thus, an experiential processing of combustion harms in the case of the Cambridge text, where climate concern is grounded in the social environment, may promote acceptable opinion and activate social norms .2.9 They could foster the belief people have violated a social custom or a legal regulation that becomes a mutually agreed upon social arrangement creating coercion and producing responsibility, with an “audience effect” enhancing the salience of the new norm. This shift would have repercussions on the individual, interpersonal, community, and public policy level where it is easier to express one's opinion, and compelling compliance of attitudes and behavior.As interdictions, warming labels could generate new discourse about “risky” gasoline consumption, indicating that more aggressive, mitigating actions are needed. Warming labels creating this meta norm can shape new social ideas and arrangements and new emotional states.10 The2.10 As a common “catastrophe narrative” the Cambridge text as negative messaging contemporaneously “strands” consumers with their current vehicle and cannot offer an immediate sense of satisfaction one has made a good environmental choice.Warming labels of inevitably uncertain environmental and public health outcomes from climate change, can undermine action rather than motivate it.1 As a However, the Cambridge public standard scheme may motivate greenhouse gas reductions through their less ambiguous, educational role grounded in public interest. Government science educating the public on combustion harms and in the absence of more aggressive government action, may be a more trusted public source of climate science information .Brewer and Ley found possible obstacles to public standard warming label efficacy where few respondents trust government but exhibited high levels of trust in individual scientists and science media .26 How3 Social norms marketing campaigns can shape social ideas, attitudes, and people's values in the immediate term. Warming labels may facilitate a collapse in trust in the current (fossil) order, moving systems from one stable state to another. Their effectiveness as market‐oriented instruments in motivating reductions in GHG emissions, will depend upon the degree to which they are understood, accepted, and credible to their audience to influence purchasing behavior and willingness to buy into a low carbon consumption context. Such schemes could include green education public service announcements and empirical pretesting that considers their “natural setting” to ensure consumers notice and interpret them correctly.Labels may address the climate policy challenge that “waiting” for the best policy in the near term increases the likelihood of severe impacts.7 Soci Consumer appraisal of the immediately unresolvable Cambridge text could increase the odds of rejection, perceiving the new government labels as a threat, and the effect of threats on attitude change can “boomerang,” producing defiance rather than compliance. Fear can motivate people to act if there are clear prescriptions and recommendations on how to act to reduce the threat of climate change.Fear, guilt, and shame have been shown to be differently motivating, and the method of coping isn't always problem‐oriented and can result in anger, retreat, and despondency.12 Con as they can't wholly resolve the requisite problem shown in the message. That said, warming labels exist in the context of other forces—the lack of low‐carbon transportation alternatives for instance—that can motivate a person to give up their fossil fuel privileges and comply with the threat of their elimination.Similarly, the Cambridge text may make individuals feel their free behaviors are being threatened48 as  Brewer and Ley point to warming labels as being less salient in rural‐conservative areas where trust in government and science is low and majorities are unconcerned about climate change. Labels targeting such subgroup areas may not be corrective of pluralistic ignorance, are likely to reduce discussion among those concerned about climate change, and thus may be unbelievable or disconfirmed to their audience.Additionally, warming labels targeting conservative audiences, may be rejected. Demographic divides—personal values, education, and income—are factors on people's low carbon consumption behavior and trust in scientific information.31 Bre Simultaneously, Republican majorities support government policies aimed at reducing the effects of climate change. Brewer and Ley results, while more reflective of general not conservative audiences, show high trust in university scientists can “spill over” to government agencies who draw on their credibility, with relatively high trust in individual scientists when respondents didn't connect scientific information to the government. Therefore, despite strong rationales and support in the prevailing literature for expecting citizens to evaluate messages about environmental science on the basis of perceived communicator credibility, it would be more useful to determine the extent to which and conditions under which, members of the public do so.Still, Brewer and Ley found conservatives express less trust in scientists than liberals, but this value was not significantly related to trust in government science.26 Sim2 emissions. Warming label programs would target cities with heavy concentrations of on‐road emissions, may activate existing normative climate concerns in these regions.Notwithstanding, we suggest warming label effectiveness may initially be most appropriate for urban areas with existing climate action planning. For instance, Gately et al. found urban areas responsible for 80% of on‐road emissions growth since 1980 are also emerging hubs of climate change mitigation activity, while continuing to produce the fastest growth in transport‐related COmissions.49 War4By activating climate concern norms, we suggest the Cambridge program as clear, public interest educational messages that do not promote narrow private industry interest, may be trusted and therefore effective in increasing self‐efficacy beliefs. This may be especially true in judging the efficacy of warming label programs that may be measured by how “ordinary citizens” engage in climate action and build the necessary, long‐term political support for furthering mitigating policies more aggressively. Label's ability to educate the public about the urgency of abiding climate‐health effects from combustion could broadly frame and outline an agenda for sustainable transport where social norms have a significant effect on the intention toward green consumerism.Vandenbergh et al. suggest label shortcomings don't obviate the value of such programs by providing better information than the consumer has at present.7 This Emphasizing individual scientist claims, for example, “Scientists say…,” warming labels may be the most trusted in producing these normative factors. This could make it easier for individuals to achieve difficult individual behavioral changes for good, while producing co‐benefits of climate policies potentially including well‐being and public health benefits from air quality improvements.Labels as present‐day focal points of climate and public health harms could push for technological innovation that leads to a competitive and social advantage.1 Emph where climate change policy is viewed as too complex and distant from the everyday lives of most people, thus increasing interpersonal talk with corresponding increases in self‐efficacy beliefs associated with long term support for emissions reductions. Labels can associate climate action with social values, where climate change includes a moral liability, since it is linked to human suffering.Warming labels can evoke more visceral reactions30 wheFuture research questions include how to mobilize largely apathetic audiences to prefer more sustainable transportation options and behaviors. A research hypothesis may state warming labels activating extant climate concern can shape public opinion toward support for more sustainable transport policies and practices. This research could explore how exposure to warming labels may increase the propensity of individuals to undertake adaptive planning ; increase realized uptake of, or intentions for, low carbon transport modes; and shape political participation or voting preferences toward support for low carbon transport. We look forward to studies linking exposure to warming labels to realized attitudinal and/or behavioral outcomes as advancing the state of the field.Regardless, the more linkages made in a way that engages experiential processing of climate effects, and minimizes psychological distance, the more meaningful and effective any such schemes are likely to be.42 We 5 This literature was reviewed to identify consistencies and inconsistencies, outlining some of the consistencies where warming labels may elevate the opinion of “alarmed” standpoints, shape climate concern norms, were experiential climate communication, and may offer an optimal level of negativity.A systematic review was conducted from 1971 through 2021 of the growing theoretical and empirical literature that investigates the relationship between social norms and climate action, based on the approach in Howe et al.42 ThiA systematic search was conducted on Google Scholar using the following key words: “public opinion,” “social norms marketing,” “climate opinion,” “carbon labels,” and “pluralistic ignorance.” The cited references in the included literature were also searched to identify possible additional publications for inclusion. The article must be published in a peer reviewed journal. Theoretical articles must describe climate opinion, public opinion, social norms, how media shape public opinion, carbon labeling, and climate change communication. Relevant articles not cited within the last five years were excluded. Empirical articles must describe or examine at least one construct related to climate opinion, efficacy of carbon labeling programs, efficacy of HWLs, or how social norms marketing could correct for pluralistic ignorance: tendency of carbon label interventions , social norms marketing programs, HWLs, and experiential learning about climate to alter preferences toward mitigation.The initial search query identified 1490 results. The search was next confined to the first thirteen pages of search results because results were sorted in descending order of search relevance. Inclusion criteria were that:Based on these criteria, 25 empirical articles and 23 theoretical were selected for inclusion. Due to a lack of efficacy data specific to warming labels, building the theoretical case to develop a scaffold for future empirical research that tests the conceptual ideas was emphasized.J.R.B. is the founder of the non‐profit Think Beyond the Pump which researches consumer public health and climate warning labels on all points of fossil purchase.


Trade‐offs between life history traits are expected to occur due to the limited amount of resources that organisms can obtain and share among biological functions, but are of least concern for selection responses in nutrient‐rich or benign environments. In domestic animals, selection limits have not yet been reached despite strong selection for higher meat, milk or egg yields. Yet, negative genetic correlations between productivity traits and health or fertility traits have often been reported, supporting the view that trade‐offs do occur in the context of nonlimiting resources. The importance of allocation mechanisms in limiting genetic changes can thus be questioned when animals are mostly constrained by their time to acquire and process energy rather than by feed availability. Selection for high productivity traits early in life should promote a fast metabolism with less energy allocated to self‐maintenance (contributing to soma preservation and repair). Consequently, the capacity to breed shortly after an intensive period of production or to remain healthy should be compromised. We assessed those predictions in mammalian and avian livestock and related laboratory model species. First, we surveyed studies that compared energy allocation to maintenance between breeds or lines of contrasting productivity but found little support for the occurrence of an energy allocation trade‐off. Second, selection experiments for lower feed intake per unit of product (i.e. higher feed efficiency) generally resulted in reduced allocation to maintenance, but this did not entail fitness costs in terms of survival or future reproduction. These findings indicate that the consequences of a particular selection in domestic animals are much more difficult to predict than one could anticipate from the energy allocation framework alone. Future developments to predict the contribution of time constraints and trade‐offs to selection limits will be insightful to breed livestock in increasingly challenging environments. This sets the direction of artificial selection.Feed efficiency: productivity output  relative to the amount of feed consumed (i.e. input). Feed efficiency metrics are generally defined either as a ratio  or as a measure of feed intake adjusted for production requirements . Feed for livestock is distinguished from food, that is feed for human consumption. Edible crops can be used as feed or food so improving feed efficiency may contribute to reduce feed–food competition.Genetic gain: for a particular trait, it is the change in average breeding value between one generation of selection candidates and the next generation only formed from the candidates that were selected and became parents.Metabolizable energy intake (MEI): the amount of energy that an animal assimilates from feed intake on a daily basis. MEI is usually calculated as the amount of feed intake times the metabolizable energy density of the diet.Productivity: the production of new biomass via growth or reproduction and measured as growth rates or rate of production by adult females : a measure of feed intake adjusted for production requirements that corresponds to the difference between actual feed intake and feed intake predicted from body mass and actual production . Individuals with lowest RFI are consistently deemed to be the most efficient.Resting metabolic rate (RMR): the lowest metabolic rate of an endotherm when one or more of the conditions required for measuring BMR cannot be met . Those changes in the energy allocation to productivity relative to the allocation to maintenance are more direct when selecting for productivity outputs while controlling for feed inputs. In this last case, we thus expect a reduced energy allocation to maintenance and repairing processes that will result in impaired health or future reproduction (prediction 2). After examining those predictions with the data currently available in the literature, we argue that the mechanisms through which productivity is selectively increased should be addressed in a more complete energy allocation framework than the current one. This appears as a key issue if we are to predict the consequences of selection for livestock bred in increasingly diverse and challenging environments.Here, we propose that the apparent absence of selection limits for increased productivity despite the existence of physiological trade‐offs illustrates a conundrum in our understanding of selection responses. Did selection for ever‐increasing rates of biosynthesis in nutrient‐rich environments lead us to overlook the existence of physiological limits to acquire and process energy, which can then favour the occurrence of energy allocation trade‐offs? To address this issue, data from livestock and related laboratory models represent a relevant starting point. Indeed, a large body of research on feed efficiency Box  of agric2Ovis aries), young breeding males suffer from an impaired survival only in years of high population density  determines which of the previous paths is undertaken during selection for increased productivity. In limiting environments  and prediction 2 , we surveyed studies in livestock species  that have investigated the genetic relationships between productivity and energy allocation to self‐maintenance. We thus performed a systemic search in Web of Science by using the following string of search terms: (‘metabolic rate’ OR ‘maintenance’ OR ‘heat production’) AND (‘line’ OR ‘breed’ OR ‘strain’) in the Web of Science categories , and using citation chaining Figure . SurprisBOX 2Manduca sexta; Figure Identifying physiological constraints at the level of genes is challenging. Focal traits under selection, such as productivity traits, are often the end products of complex genetic, physiological, developmental and endocrine processes. The biological complexity in the mapping of genotype to phenotype can be reduced by focusing on mechanistic traits, which usually refer to a small number of physiological traits that determine focal traits. To assess the extent to which those mechanistic traits constrain or enable selection responses, laboratory selection experiments exploring multiple directions of selection are relevant tools Garland, . If in aTwo focal traits of larva development to pupation were artificially selected: development time and pupal weight. Those traits can be predicted from their functional relationships with three mechanistic traits , length of the growth period (ICG) and growth rate (GR)) that characterize the last stage of larva development into pupae:Predicted pupal weight = CW + (ICG × GR),Predicted development time = ICG + (CW/GR),where the attainment of the CW marks the transition from the juvenile growth to the reproductive adult phase , ICG corresponds to the duration of the period of growth from CW to pupal weight, and GR refers to the linear rate of change in body weight during this stage.Both CW and ICG have positive effects on development time and pupal weight, whereas GR has a positive effect on pupal weight and a negative effect on development time. Pupal weight and development time were simultaneously selected to explore four directions (i.e. same or opposite directions). Regression lines in Figure 3.1i’), and those related to maternal reproductive outputs such as litter size or milk yield in mammals (Table i’). As for energy allocation to self‐maintenance, it cannot be approximated by BMR when animals are in a production phase. We considered instead any measure of RMR (Box 0.75), but we also found studies that simply reported mass‐specific estimates and others that used covariance analysis with body mass as covariate, as recommended by integrative physiologists  did not detect any difference in maintenance energy metabolism between animal groups with contrasting growth rates . However, there was little information on the persistence of those associations beyond the growth period in these determinate growers . In contrast, evidence for positive associations between maternal productivity and RMR was also observed when adult females were not reproducing (e.g. studies R3–R5). Still, the detection of associations is inevitably hindered by the limited data relative to the large number of factors, notably caused by the use of various metrics to measure RMR.3.2i’). Indeed, in the livestock context, feed efficiency and related metrics such as residual feed intake (Box 0.75 (Exp. M7) or mass‐independent BMR (Exp. M8)) has a positive selection response on feed intake , the energy used for self‐maintenance and dissipated as heat is more challenging to estimate and to interpret functionally, particularly when animals are in a productive phase Figure . Just ascy Table  and thatcy Table .ad libitum access to nutrient‐dense feed is commonly considered as a main reason for the absence of trade‐off  or by selecting for a composite trait  when chickens are increasingly fast‐growers Figure . These cIn our survey, support for the ‘independent’ or ‘increased‐intake hypothesis’ (paths 1 and 2, respectively, in Figure 4.3Although physiological constraints on energy intake and expenditure remain elusive, this does not preclude a physiological restraint that is evolutionary shaped due to the fitness costs of a high intake (Speakman & Król, In livestock, evolutionary hypotheses on the control of feed intake have received some attention (Illius et al., Viewing the physiological control of feed intake as a target of selection is also in line with incentives to consider more explicitly signalling pathways in the resource allocation framework Glazier,  and in b5Observations in livestock do not conflict with the compelling evidence that supports resource allocation in the broad sense—that is the fact that changes in energy and material apportioning are part of selection responses. As observed in our study, genetic changes in energy allocation to maintenance are clearer when feed intake is part of the selection objective than when selection is simply based on a productivity trait. However, livestock data question the nature and the importance of resource allocation constraints in the narrow sense Glazier, —that is In particular, recent evidence from experiments performed on laboratory organisms has revealed that somatic maintenance can be improved at no fitness cost when nutrient‐sensing pathway is downregulated during adulthood (e.g. Carlsson et al., Although livestock populations are often bred in relatively uniform and controlled environments, the large amount of data collected on these biological models offers a largely untapped opportunity to bridge research on physiological trade‐offs with population genetics. For instance, Schou et al.  used estFinally, although continuous improvement in livestock productivity seems feasible from the perspective of quantitative genetics Hill, , there iThe authors declare no conflict of interest.Supinfo S1Click here for additional data file.


IMAPI represents the first attempt to select nurturing care indicators at the municipal level using data from existing routine information systems.The Nurturing Care Framework (NCF) calls for establishing a global monitoring and accountability systems for early childhood development (ECD). Major gaps to build low‐cost and large‐scale ECD monitoring systems at the local level remain. In this manuscript, we describe the process of selecting nurturing care indicators at the municipal level from existing routine information systems to develop the Brazilian Early Childhood Friendly Index (IMAPI). Three methodological steps developed through a participatory decision‐making process were followed. First, a literature review identified potential indicators to translate the NCF domains. Four technical panels composed of stakeholders from federal, state and municipal levels were consulted to identify data sources, their availability at the municipal level and the strengths and weakness of each potential indicator. Second, national and international ECD experts participated in two surveys to score, following a SMART approach, the expected performance of each nurturing care indicator. This information was used to develop analytical weights for each indicator. Third, informed by strengths and weaknesses pointed out in the previous steps, the IMAPI team reached consensus on 31 nurturing care indicators across the five NCF domains (Good health [ The Nurturing Care Framework (NCF) calls for establishing monitoring systems for early childhood development (ECD) to achieve the 2030 Sustainable Development Goals.A three‐step participatory methodological process was designed and piloted to select municipal‐level nurturing care indicators using a routine information system.Brazil is an important country to identify municipal‐level nurturing care indicators because the implementation of ECD programmes happens across its 5570 municipalities in the context of great inequities.The Brazilian Early Childhood Friendly Municipal Index (IMAPI) represents the first attempt to select nurturing care indicators at the municipal level using existing routine information systems.1Optimal early childhood development (ECD) follows a gradual process that is contingent on children and their families having access to nurturing care environments needed by children to reach their full motor, language, socio‐emotional and cognitive development .In this context, Brazil, which is the largest and the most populous country in Latin America (with 211 million inhabitants), provides an important opportunity for testing a municipal‐level ECD index because the operationalization of ECD programmes occurs across 5570 municipalities in the context of great socio‐economic and environmental disparities  as well as non‐government institutions (n = 4). Each institution could determine and recommend one or more participants based on the technical panels' goals. Although the number of participants varied across technical panels, all invited institutions sent at least one participant. Technical panel participants were individuals that managed or had in‐depth knowledge of national databases with information about health, education and social development in Brazil. In Step 2, expert surveys were designed to validate the selection of municipal‐level nurturing care indicators and score each of the SMART attributes to inform an evidence‐based analytical weight per indicator. Invited experts were identified within the Brazilian and international institutions and networks highly engaged with ECD programming in Brazil. Expert surveys' participants included individuals with experience in ECD and public policy, who had in‐depth knowledge of the socio‐economic, geographical and political context of Brazil. Fourteen experts were invited by email, and 12 accepted the invitation to participate. Of those, 11 experts participated in the first survey, and seven in the second survey. In Steps 1–3, the IMAPI team engaged throughout the participatory decision‐making process. Each of the four rounds started with an input statement, which consisted of a list of nurturing indicators named ‘ECD Indicators Versions 1–4’ produced by the IMAPI team. At the end of each round, this list of nurturing care indicators was revised by the IMAPI team to summarize modifications and consensus within that round, which generated an output statement, which, in turn, became the input statement for the next round. The IMAPI team was composed of the principal investigators, research assistants and senior advisors who collectively had expertise in epidemiology, maternal–child nutrition, implementation science and data science and machine learning.Technical stakeholders, experts and the IMAPI team engaged in the different steps of the participatory decision‐making process Figure . Detail Good health , Adequate nutrition , Responsive caregiving (indicators related to family skills and child care in the home environment), Opportunities for early learning  and Security and safety (indicators related to protections or vulnerabilities to which the child may be exposed in the family or community environment). Indicators considered important for placing the NCF into the diverse municipal contexts were allocated to the category of ‘additional indicators’ (e.g. population size and the region of the country), which also underwent revisions, additions or removal following the same methods followed for the selection of the nurturing care indicators. Second, in Round 1, the IMAPI team discussed the ‘ECD Indicators Version 1’ based on the following questions: (i) Does the indicator evaluate the enabling environment for ECD in one of the five domains of NCF? (ii) Does the indicator complement information about the enabling environment for ECD? (iii) Which of the five NCF domains does the indicator belong to? (iv) Does the indicator need to be modified or removed as it does not suit the Brazilian municipal context? These questions guided the IMAPI team to reach a consensus on modifications to each indicator. At the end of this round, the IMAPI team summarized the consensual modifications that generated a revised list of nurturing care indicators, the ‘ECD Indicators Version 2’ , as well as list possible weaknesses of each indicator and suggestions of potential new indicators. Consensus was reached when participants in the technical panels did not have more concerns or suggestions about an indicator or NCF domain. At the end of this round, the IMAPI team summarized the consensual modifications that generated the ‘ECD Indicators Version 3’  based on a careful review of documents and technical materials measuring actions and policies for early childhood, such as Countdown 2030, World Bank, World Health Organization, NCF website and São Paulo Early Childhood Index (IPPI)  assessed the specificity of each indicator allocation across the NCF domains and was confirmed by the percentage of agreement among experts. This information was used to assure appropriate weighting procedures by confirming the appropriate allocation of each indicator in the NCF domain. Experts' consensual modifications or suggestions regarding the indicators were summarized by the IMAPI team in the ‘ECD Indicators Version 4’  to 5 (highest) the importance of four quality attributes for each indicator: periodicity of data (M1 Periodicity), data source (M1 Source), access to data (M1 Access) population profile (M1 Population profile). Then, the four quality attributes were assessed for each indicator by the IMAPI team by scoring 1 (lowest) to 5 (highest) . Criterion M for each indicator consisted of the average of M1 and W1 of each quality attribute. The second survey consisted of scoring A, R and T criteria from score 0 (lowest) to 5 (highest) in relation to governance needed for modifying the nurturing care indicators for achieving greater impact on ECD outcomes at the municipal level , the extent to which changes in the indicators have the potential to directly impact ECD  and the time that improvements in an indicator would take to positively impact ECD .This step aimed to estimate an analytical weight for each municipal‐level nurturing care indicator following a SMART process. Because the NCF assumes that all domains have the same level of importance, the purpose of the analytical weighting exercise was to improve reliability when generating IMAPI indexes by giving higher performance analytical weight to indicators with better data quality attributes Köhler, . Additio’ Figure . CriteriSurvey analysis informed the development of the formula to estimate the analytical weight per nurturing care indicator  to 5 (high) performance. The average of M, A, R and T criteria for each domain was used to identify indicators with best quality performances (i.e. greater than the mean of the domain) and worst performances (i.e. less than the mean of the domain) by NCF domains. Any indicator added after the determination of SMART analytical weights received the average analytical weight of the domain the new indicator was allocated, as indicated in Table or OECD, , as follRound 4, the IMAPI team discussed the indicators listed in ‘ECD Indicators Version 4’ and summarized strengths and weaknesses for each indicator pointed out in the previous steps by the technical panels and expert surveys , Adequate nutrition (n = 3), Responsive caregiving (n = 6), Opportunities for early learning (n = 4) and Security and safety (n = 6) . Greater importance was given to the attribute population profile (i.e. population representativeness) (mean = 4.55), followed by access to data (4.45), periodicity (4.20) and data source (4.09). Most indicators had national representativeness (n = 24 out of 31), and if they were available for download via the Internet (n = 22) at least once per year (n = 23), they received the highest scores for population profile, data access and periodicity, respectively. Only two indicators (‘household food insecurity’ and ‘air pollution’) were cross‐sectional research projections  and for this reason received the lowest scores for data source . Changes in 18 indicators out of 31were considered achievable within the municipal‐level governance ; 14 indicators were considered more relevant for changes in ECD ; changes in 17 indicators were considered to lead to short‐term ECD outcome improvements . Final analytical weights for each indicator were generated  (Box 1). Thirteen additional indicators not allocated into NCF domains were also selected to characterize municipalities' context .Table Box 1. Standard definitions of the selected indicators composing the Brazilian Early Childhood Friendly Municipal Index (IMAPI)4As far as we know, IMAPI represents the first attempt to identify nurturing care indicators at the municipal level using routine information systems. Although other experiences measuring the environment for ECD SEADE,  or childRooted in the evidence‐based NCF, our approach to identifying nurturing care indicators was a result of a stepwise participatory decision‐making methodology including a carefully selected group of multisectoral stakeholders and experts. This participatory process was efficient as it led to (i) the identification of indicators already used to monitor child health as well as access and quality of services in routine information systems, (ii) the inclusion of SMART properties for the stakeholders or end users of IMAPI in the calculation of the index and (iii) the consideration of the attributes of quality and limitations of each indicator.The use of a participatory decision‐making methodology was a strength of IMAPI. Participatory decision‐making and consensus processes can effectively help stakeholders reach consensus through trust and learning within a reasonable time on a valid outcome , which collects continuous information about nutritional status and food consumption of children and adolescents receiving primary healthcare services  use of a data engineering approach to create an index for each domain as well as a single index of the NCF and (ii) analysing whether IMAPI indexes can discriminate nurturing care environments across the 5570 municipalities in Brazil, which are described elsewhere.GB, MEB and MBG conceptualized the Brazilian Early Childhood Friendly Municipal Index (IMAPI) and designed the participatory decision‐making method with intellectual inputs of RPE and SIV throughout the process. JP, SC, GFC, AS, JB and JG conducted activities within the participatory decision‐making method and analysed the data. GB wrote the first draft of the manuscript, and MBG, MEB, RPE and SIV revised it critically through an iterative process. All authors approved the final version of the manuscript.The authors declare no conflicts of interests.Table S1. List of institutions represented at panellists groups in the participatory decision‐making process.Click here for additional data file.Table S2. History of nurturing care indicators during the participatory decision‐making process of the Brazilian Early Childhood Friendly Municipal Index (IMAPI).Click here for additional data file.Table S3. Methodological note on the SMART criteria definition, classification and analysis.Click here for additional data file.


Progestogens  are widely recommended for women at high risk of preterm birth. Typical regimens include 17‐hydroxyprogesterone caproate (250 mg intramuscularly weekly), starting at 16–20 gestational weeks until 36 weeks or delivery for women with a singleton gestation and a history of spontaneous preterm birth, or vaginal progesterone  for women with a short cervix . Although some randomized trials support this approach, neither of the largest trials  demonstrated efficacy. There are almost no data on long‐term effects, and none that shows benefit beyond the neonatal period. Although some analyses suggest the cost‐effectiveness of the approach, a cervical length screening program followed by progesterone for those with a short cervix will reduce preterm birth rates by less than 0.5%. The present review assesses evidence on the efficacy, likely impact, and long‐term effects of implementing the recommendations for progestogens in full. Clinicians and pregnant women can look forward to resolution of the conflicting views on efficacy once the Patient‐Centered Outcomes Research Initiative (PCORI)‐funded individual patient data meta‐analysis is published. The efficacy, probable impact, and long‐term effects of progesterone or 17‐hydroxyprogesterone acetate on the prevention of preterm labor are uncertain. This can be done at the same time as the ultrasound performed for the anatomical survey  diagnosed in the mid‐trimester should be offered daily vaginal micronized progesterone treatment for the prevention of preterm birth and neonatal morbidity.”“The progesterone formulation to be used is vaginal micronized progesterone  nightly or vaginal micronized progesterone gel (90 mg) each morning.”“Universal cervical length screening and vaginal progesterone treatment  is a cost‐effective model for the prevention of preterm birth.”“In cases in which a transvaginal ultrasound is not available, other devices may be used as a screening tool to measure objectively and reliably the cervical length.”The importance of progesterone in the maintenance of pregnancy is well established and applies across many species. Indeed, the term “progesterone” is derived from the phrase “progestational steroidal ketone.” In 2015, the International Federation of Gynecology and Obstetrics (FIGO) working group on the best practice in maternal fetal medicine published a guideline endorsing the use of progesterone to prevent preterm birth for selected women.The aim of the present review is to discuss the rationale for these recommendations, their likely impact, and whether they should be updated in the light of new evidence.2Progesterone clearly plays a role in the maintenance of pregnancy. Circulating levels of progesterone rise during pregnancy: the major source (in humans) is the corpus luteum until approximately week 8 of pregnancy, and the placenta thereafter. One of the major mechanisms of progesterone action in maintaining pregnancy is inhibition of the contractions of the myometrium: research has demonstrated the relaxant effect of progesterone on myometrial strips in vitro.The importance of progesterone in maintaining human pregnancy in vivo has been demonstrated by studies administering receptor antagonists such as mifepristone (RU486). If administered in early pregnancy, mifepristone increases uterine contractility in vivo,So, what is the evidence on which the FIGO recommendations for progesterone prophylaxis in women with a short cervix are based? To address this question, it is necessary to consider the efficacy of progesterone, the impact of such a strategy on a population basis, and the long‐term benefits and harmful effects of progesterone treatment in pregnancy.3The most recent Cochrane review on progesterone for the prevention of preterm birth (published in 2013) examined evidence on the use of any progestogen for women at risk of preterm birth either because of a previous preterm birth or because of a short cervix.For women with cervical shortening the review found that, among the above outcomes, only preterm birth before 34 weeks was reduced by progestogen .Further analyses in the review found no differential effects in terms of route of administration, time of commencement of therapy, or dose of progesterone for the majority of outcomes examined.+0 and 20+6 gestational weeks, and continued until 37 weeks or delivery (whichever is earlier). Supporting evidence for the licensing of intramuscular 17‐hydroxyprogesterone caproate were provided by the trial of Meis et al.Importantly for clinicians and for pregnant women, the regulatory status of the different progestogen formulations given for preterm birth differs. Intramuscular 17‐hydroxyprogesterone caproate (Makena) is licensed by the US Food and Drug Administration (FDA), but not the European Medicines Agency (EMA), to reduce the risk of preterm birth for women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The product license refers to a dose of 250 mg, administered intramuscularly once per week, starting between 16+0 to 20+6 gestational weeks until 37 weeks or delivery (whichever is the earliest). The two co‐primary efficacy endpoints were preterm birth before 35 gestational weeks and a composite index of neonatal morbidity and mortality.Although the FDA provided a license, a component of approval was the requirement for a confirmatory trial.The results of the PROLONG study were published in October 2019.Commentators have had a mixed reaction to publication of the PROLONG study. The FDA advisory committee has suggested that 17‐hydroxyprogesterone acetate should be withdrawn from the market for the prevention of preterm delivery, although this decision has not yet been finalized. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal and Fetal Medicine (SMFM) have both noted that women enrolled in the PROLONG trial were at lower risk for preterm birth as compared with those in the trial of Meis et al.+0 to 23+6 gestational weeks were randomized either to vaginal progesterone (90 mg) or placebo. The primary outcome was delivery before 33 weeks, and 235 and 223 women were available for follow‐up in each group. The progesterone group showed a significant reduction in the rate of preterm birth before 33 gestational weeks  and in neonatal outcome as a composite of adverse events . Among the individual components of neonatal outcome, only a reduction in respiratory distress syndrome was statistically significant .In contrast to 17‐hydroxyprogesterone caproate, vaginal progesterone is not licensed for preventing preterm birth in the United States. A submission to the FDA was prepared from data generated by a large randomized trial conducted in the United States and elsewhere.Having reviewed the data from that study, the FDA chose not to provide a license for vaginal progesterone for preterm birth prevention. The FDA notes accompanying their decision state: “the statistical test used by the ‘applicant’ was inappropriate because of insufficient sample size in each strata and inconsistent treatment effects within strata,” that “the first dose, maternal age, cervical length, body mass index, and race differed notably by region,” and that “after adjusting for these covariates, the effect of progesterone in reducing preterm birth was not statistically significant”.improve obstetric outcome by lengthening pregnancy and thus reducing the incidence of preterm delivery (before 34 weeks);improve neonatal outcome by reducing a composite of death and major morbidity;lead to improved childhood cognitive and neurosensory outcomes at 2 years.Two large studies published since the Cochrane review in 1913 did not find a positive effect of progesterone in preventing preterm birth. For women at high risk of preterm labor, the OPPTIMUM study+0 and 24+0 gestational weeks, combined with a history in a previous pregnancy of any of the following: preterm birth, second‐trimester loss, premature fetal membrane rupture, or a cervical procedure to treat an abnormal smear test. In addition, women with a history of a previous spontaneous preterm birth before 34+0 weeks and those with a cervical length of 25 mm in the index pregnancy were eligible regardless of the fetal fibronectin test result.The double‐masked placebo‐controlled randomized OPPTIMUM trial was conducted among 1228 women at high risk of preterm birth at 65 UK National Health Service (NHS) hospitals and one Swedish hospital between February 2009 and April 2013.P values for the three primary outcomes are summarized in Table The odds ratio (OR), 95% CI, and P=0.912).Subsequently, the PROGRESS studyThus, there are clearly conflicting data about the efficacy of progesterone for preterm birth prevention.To address this controversy, the Patient‐Centered Outcomes Research Initiative (PCORI) has commissioned a prospective, independent comprehensive, high‐quality, individual patient data meta‐analysis on the efficacy of progesterone for preterm birth prevention. Researchers from all studies evaluating the efficacy of progestogens for preterm birth prevention have been invited to submit their data. The results are expected in early 2020, and it is likely that this project will give the most authoritative estimates of the efficacy of progesterone for preventing preterm birth and its consequences for women at high risk.4Many groups have evaluated the cost‐effectiveness of routine cervical length scanning to identify women with a short cervix, combined with prescribing progesterone for preterm birth prevention.The overall analysis suggested that a policy of routine cervical length scanning  combined with progesterone prophylaxis for 0.85% of women with a short cervix would be cost‐effective in the United States. It would require 2.19 million vaginal sonograms, and the prescription of vaginal progesterone for 11 027 women annually; however, there would be 913 fewer preterm births and 63 fewer neonatal deaths. The total cost would be US $52 million annually. Given the costs accruing from adverse outcomes due to prematurity, the “no screen” option was most expensive. Risk‐based screening was the least expensive option, but universal screening was most cost‐effective, with an incremental cost‐effectiveness ratio of US $21 144 per quality‐adjusted life year.Regardless of its cost‐effectiveness, the impact of universal cervical length screening on the rate of preterm births is trivial in the context of the overall preterm birth rate. In 2014, there were 381 659 preterm births in the United States; thus, prevention of 913 births would reduce the rate of preterm birth from 9.57% to 9.55%. Performing a similar analysis in France, Rozenberg has described this as the inverse of the Pareto principle—in other words, a large amount of effort for a small gain.There are other challenges in providing universal cervical length screening. The sonogram “cost” of US $73.47 described above probably does not include training, quality‐control programs, or equipment. In addition, without extensive training of additional providers, there will be insufficient availability of cervical length scanning to perform this analysis on a population basis. Furthermore, reproducibility is limited even when experienced observers perform measurements under standardized conditions.5Clinicians and pregnant women wishing to use progesterone to prevent preterm birth need to be aware of the long‐term risks and benefits. The primary rationale for preventing preterm birth is to avert adverse consequences for the newborn. Worldwide, 15 million preterm births per annum result in around 2000 neonatal deaths, and neurodevelopmental disability in nearly 1 million survivors.A good example of this is the ORACLE II randomized trial of antibiotics to prevent preterm birth among women presenting with signs and symptoms of preterm labor, but with intact fetal membranes. Although there were no major differences in outcome in the short term ,P=0.087).Regarding singleton pregnancy, only two studies have examined the long‐term effect of progestogens. The follow‐up to the study of 17‐hydroxyprogesterone caproate by Meis et al.66 gestational weeks receive 17‐hydroxyprogesterone caproate (250 mg intramuscularly weekly) starting at 16–20 weeks until 36 weeks or delivery for women with a singleton gestation and a history of prior spontaneous preterm birth.The National Institute of Clinical Excellence in the United Kingdom,As discussed in this review, however, the evidence on efficacy for those at risk of preterm birth, impact on preterm birth rates, and long‐term effects for the baby of implementing these recommendations remains inconclusive. Clinicians and pregnant women can look forward to some resolution of the conflicting views on efficacy once the PCORI‐funded individual patient data meta‐analysis is published. Recommendations should be updated once the full details of the PCORI individual patient data meta‐analysis is in the public domain.JN wrote and revised this article, and is responsible for the final version.The author has received funding from government and charities for research on preterm birth, stillbirth, and obesity in pregnancy. She is on a Data and Safety Monitoring Committee for GlaxoSmithKline for a trial of an agent to treat women in preterm labor, was the Chair of the NICE guideline development committee on Preterm Labor and Birth (pub. Nov 2015), and received funding from NIHR for the OPPTIMUM study of progesterone for the prevention of preterm birth.


Articular disc displacement is the most common temporomandibular joint (TMJ) arthropathy . Disc diFemale patient, 38 years, with signs and symptoms of TMD presents a clinical diagnosis of right TMJ DDwoR and left TMJ subluxation, according with the Diagnostic Criteria for Temporomandibular Disorders protocol (DC/TMD). The initial pain free opening (PFO) was 31 mm with an uncorrected deviation to the right side in terms of opening pattern. Interdisciplinary team composed by two dentists and two physiotherapists decided the following strategy: assessment of PFO and opening pattern (DC/TMD examination form) before and after any intervention. After the initial assessment we had the first session of PT to prepare for the VS composed of behavioural and cognitive therapy, manual therapy, motor control exercises and prescription of home exercises. One week after we performed the first session of VS with 1 ml of high molecular weight hyaluronic acid bilaterally in the TMJ followed by another session of PT. Two sessions were performed, once a week, in two consecutive weeks. All the assumptions of the Helsinki Declaration have been fulfilled and an informed consent for clinical case of Clínica Dentária Egas Moniz approved by the ethic commission of Instituto Universitário Egas Moniz.Data was collected before and after any intervention. In first session of PT, PFO measurements increased from 31 mm to 38 mm and opening pattern remained a right uncorrected deviation. After the VS and second PT session the PFO increased from 35 mm at the beginning of the intervention to 45 mm at the end and the opening pattern changed to a straight opening pattern.VS has been proven to be effective for knee and other large joints . Studies


Thank you Barkas et al. for your interest in our article titled “A novel study on SARS‐COV‐2 virus associated bradycardia as a predictor of mortality‐retrospective multicenter analysis.”The possible mechanism for remdesivir causing bradycardia is still up for debate. The active metabolite is a nucleotide triphosphate which is a derivate similar to adenosine triphosphate (ATP).In the future, we agree with Barkas et al. that remdesivir and development of bradycardia needs to be investigated further. Touafchia et al. used the WHO safety report database reported a 31% incidence of bradycardia in those individuals receiving remdesivir. 75% of patients with bradycardia went on to develop serious complications including death.Barkas et al. bring up a good point on the relationship between onset of remdesivir exposure and development of bradycardia. Remdesivir has a high affinity to bind to viral polymerases; however, there is a chance for cross‐reactivity with human mitochondrial RNA polymerase, which could lead to mitochonridal dysfunction and subsequent cardiomyocte toxicity. Choi et al. showed that the cytotoxic effects of remdesivir increased overtime (48 hours vs. 24 hours), in addition to reducing cell viability.Multiple case reports have also discussed remdesivir‐causing bradycardia.We are in the process of pursuing a retrospective analysis looking specifically at the timing of remdesivir and subsequent bradycardia. We invite anyone to send a message to the corresponding author if they want to collaborate on our study.The author(s) declare no conflict of interest for this work.