Further, we discuss the relevance of studying tempo for tissue transplantation, homeostasis and lifespan.Time is inherent to biological processes. It determines the order of events and the speed at which they take place. However, we still need to refine approaches to measure the course of time in biological systems and understand what controls the pace of development. Here, we argue that the comparison of biological processes across species provides molecular insight into the timekeeping mechanisms in biology. We discuss recent findings and the open questions in the field and highlight the use of  This is particularly obvious during embryonic development where the sequence and rate of events ensure that structures develop in the right place at the right time. Importantly, the speed of these processes (tempo) controls the rate of development of the whole organism and ultimately the length of time embryogenesis takes. Modifying the pace of development can affect the final size and composition of tissues in a growing organism. Imbalances in the speed of tissue development and stem cell differentiation can result in tissue overgrowth or deficits. Therefore, controlling the speed of differentiation is essential for the size, function and shape of developing organisms.Biological clocks need to keep track of multiple timescales, and cells need to be in synchrony to build tissues and organs during development and homeostasis. How tempo is encoded in the genome and how organisms coordinate the development of different organs remain unknown. Growing evidence suggests that tempo can be set by autonomous mechanisms in individual cells during development ,2, but lIn silico models and simulations from experimental data using dynamical systems theory can be used to investigate how GRNs dynamically work [Gene regulatory networks (GRNs) play a central role in development. Gene expression programmes are controlled by transcriptional regulators that, together with the cis-regulatory elements to which they bind, integrate external cues and coordinate the spatial and temporal elaboration of developmental programmes . Experimlly work . Moreovelly work . TherefoA fascinating but complex aspect of temporal control is how different developmental processes are regulated at different scales . Transcrin silico models will offer insight into how developmental processes generate evolutionary scalable and robust temporal patterns.One promising approach is to take advantage of the evolutionary conservation of developmental mechanisms and GRNs. Highly conserved GRNs that operate at different speeds in different species permits a search for the properties that might explain differences in tempo. Conserved GRNs are composed of the same regulatory interactions and the same transcription factors. Therefore, the dynamics of molecular processes  can be measured and parametrized using dynamical system models to investigate temporal aspects in the GRN. This provides a means to explore how conserved GRNs operate proportionally at different speeds and what the dynamic limits might be. Overall, measurements and perturbations of conserved GRN kinetics combined with . 2During development, the phylotypic stage corresponds to the period of development when embryos manifest the archetype of the vertebrate body plan and hence different species closely resemble one another . This stThe rate at which embryos from different species progress through the phylotypic stage is species-specific. Since each species develops at a different pace, comparisons between developmental processes at the phylotypic stage are an attractive system to study tempo control. Recently, two papers have taken a comparative approach across species in developmental processes that take place at the phylotypic stage to study tempo: somitogenesis and motor neuron formation in mouse and human embryos .in vitro in tissue derived from the directed differentiation of pluripotent stem cells [in vitro models of the segmentation clock from mouse and human retain the differences in oscillation periods, they can be used to interrogate what determines these differences in the oscillation period. In an effort to understand the mechanism that explains the differences in tempo, Matsuda et al. [One process characteristic of the phylotypic stage in vertebrates is somitogenesis—the process by which mesodermal cells rhythmically produce pairs of segments along the axis that will give rise to muscle and axial skeleton . This inem cells –18. Sinca et al.  showed ta et al.   to CS9 (day 18–21) [The recent development of three-dimensional stem cell differentiation models, termed gastruloids, offers new possibilities to compare developmental progression and coordination between tissues in mouse and human . These im layers –32, enab to E9.5 . The temy 18–21) ,31. The Xenopus animal caps and explants of whole zebrafish embryos, termed pescoids, have been shown to maintain the same self-organizing properties as mammalian cells . Compari. 4The phylotypic stage arises as the most constrained period of development, requiring the coordination of molecular and morphological processes in the entire embryo . As a co. 5ex vivo for long periods of time (up to 4 days in mouse) [Upon fertilization, the single-cell zygote undergoes multiple rounds of cell divisions without an increase in mass (this is termed cleavage) and forms a ball of cells called the blastula. Embryos at this stage can self-organize without the need for external cues and can be grown n mouse) . MoreovePre-implantation development follows similar morphological states across mammals and results in the formation of a fluid-filled blastocyst. Several perturbation experiments suggest a cell intrinsic control of tempo. Removal of one blastomere from the two-cell embryo in mouse embryos, halving the size of the embryo, leads to the formation of a smaller blastocyst that cavitates at the same time as full embryos .Likewise, dissociated cells from the eight-cell embryo temporally progress at the same rate as intact embryos . HoweverDespite the divergence in genome activation and gene expression patterns, the morphological changes during pre-implantation development are remarkably conserved across species. These morphological changes correlate with the timing of other developmental events such as lineage specification and progress cell autonomously. Morphokinetic analysis using time-lapse imaging in mouse and human embryos from the eight-cell stage up to the blastocyst stage allows for an accurate comparison of developmental progression. The analysis shows that mouse embryos take 12 h from the time of compaction to the formation of an early blastocyst, with a single dominant cavity, whereas it takes 24 h (a twofold difference in tempo) for the same process to occur in human embryos .The twofold tempo difference in morphological changes between mouse and human raises the possibility of allochrony during pre-implantation development. The conservation of allochrony for morphological changes in the system despite the divergence in the GRNs might indicate that there are mechanisms that preserve tempo throughout development. It would be interesting to determine whether protein turnover during pre-implantation development is slower in human compared to the mouse as described for the phylotypic stage.. 6Limbs represent one of the best-studied systems in evolution and development. Although they show a well-defined sequence of temporal events, such as the proximo-distal patterning of the limb bud and the chondrification of skeletal elements, they have undergone extensive evolutionary diversification in different species . Some ofAs limb development proceeds, paired limbs develop to attain a characteristic morphology that ultimately defines the identity of a forelimb (arm) or a hindlimb (leg). The earlier stages in limb development take place during the phylotypic stage, and fore- and hindlimb expression patterns diverge at later stages of development . The dis. 7The neocortex is the outer layer of the cerebral hemispheres and is unique to mammals. The neocortex has undergone substantial morphological transformations during evolution and shows a high degree of variation across mammals. It comprises six distinct layers of neurons that display specific patterns of gene expression and connectivity . The layin vivo and in stem cell models/organoids of corticogenesis across species [In contrast with the spinal cord, corticogenesis occurs over a protracted period in development, starting at mid-gestation stages and lasting until around birth in the mouse . Recent  species –58. Thes species . In addiDifferences in tempo can also be measured independently of gene expression. A recent study comparing structural and functional maturation of neurons across primates shows that human-induced neurons develop slower than chimpanzee and bonobo neurons in terms of their electrophysiology and dendritic arborization . SimilarTaken together, the available evidence suggests that there are proportional scaled changes in the pace of development  during cleavage and the phylotypic stages, and that regulatory divergence observed in early stages maintains the allochrony of the system. By contrast, species-specific differences arising from other forms of heterochronies emerge at late stages of development and contribute to morphological variation . Studyin. 8Nothobranchius furzeri) uses diapause to survive long droughts. Killifish diapause embryos contain differentiated tissues from the three embryonic germ layers. It has been shown that the survival of the embryos preserves the organism for extremely long periods without trade-offs for adult growth, fertility and lifespan [C. elegans [Diapause is the delay in development initiated in response to adverse environmental conditions. It is a widespread physiological process in the animal kingdom where the developmental clock is stopped and then restarted . How thilifespan . Diapaus elegans , suggestin vitro [in vivo versus in vitro comparisons. Partial inhibition of mTOR, which is regulated by amino acid levels, induces reversible pausing of mouse blastocyst development [Some mammals also undergo diapause at the blastocyst stage, prior to gastrulation. This can be initiated as a response to cues indicating an adverse environment with development being resumed once environmental conditions improve . In mousin vitro ,65. Thiselopment ,66. The . 9Xenotransplants, in which cells are transplanted from one species to another, provide evidence that in many cases developmental tempo is set cell autonomously. A recent report examining tempo mechanisms showed that zebrafish retina xenotransplanted in medaka resulted in a temporal decoupling between the donor retina and the host, supporting a species-specific autonomous tempo in biological systems .Given the differences in tempo across species, it is worth reviewing the available knowledge in transplantation experiments used for disease modelling, replacement therapy or to generate human organs in animals for transplantation purposes.. 9.1Hematopoietic stem cells (HSCs) have the capacity to restore the entire hematopoietic system upon transplantation into a suitable recipient. The grafting of both mouse and human HSCs into immunodeficient mice has enabled the study of HSCs. The grafting efficiencies of human cells in mice are relatively low compared to the efficiencies associated with mouse–mouse transplants. This could be related to the state or the type of transplanted HSCs . However. 9.2In vitro differentiation models to study cortical neuron development are technically challenging because of the long-term maintenance of functional neurons. Therefore, xenotranplantations of human neurons into the mouse brain provide a means to study neuronal maturation under physiological conditions [in vitro studies. Despite the differences in the speed of progression, human neurons make synaptic connections in the mouse brain and respond to sensory stimuli in a similar fashion to host neurons.Despite the relevance for brain evolution and diseases, the development of human neurons and circuits remains poorly understood. This is in part due to the challenge of studying live human neurons in the context of a brain circuit. nditions . Embryonnditions ,72. Humanditions ,74, indi. 9.3Macaca fascicularis) stem cells are injected into pig blastocysts, only one in 1000–10 000 is from monkey origin [Growing human organs in animals has received recent attention for transplantation purposes. One way this is achieved is by interspecies blastocyst complementation, where human pluripotent stem cells are injected into embryos from other species to generate chimeras. A puzzling question in these experiments has been the varying degrees of chimerism success . It is ay origin . One pos. 10Organ homeostasis and regeneration in tissues such as skin, muscle, gut, liver, lungs, pancreas or blood depends on the balance between the proliferation and differentiation of tissue-resident stem cells in response to the environment, imbalances leading to ageing and disease. Controlling the dynamics of these processes is therefore essential to maintain functional organs in adult animals. As stem cell proliferation and differentiation are common mechanisms in the developmental and homeostatic process, differences in the speed of progression might exist across species during adult homeostasis.in vitro culture systems, generally referred to as organoids. Organoids have been successfully obtained from mouse and human stomach, intestine, colon, lungs, pancreas, kidney and liver. Gastrointestinal organoids retain their self-renewing and differentiation potential, and their spatial organization recapitulates the in vivo organization of the epithelial intestine. Stem cells populate the base of bud-like structures and mature cell types migrate to the central structure of the cyst [The identification of mechanisms governing the regeneration and homeostasis in tissues has allowed the production of these tissues in three-dimensional the cyst . The spethe cyst . It woulin vitro systems offer an unprecedented opportunity to investigate cell-autonomous and coordinated mechanisms responsible for the speed of progression. Whether the differences in developmental tempo between species reflects differences in the homeostatic processes that maintain mature organs in adult animals remains to be determined. The ability to understand the pace of progression during homeostasis may in turn allow us to speed up or slow down stem cells and optimize organoids for therapeutic applications and drug discovery. In addition, it might also provide insight relevant for slowing tumour growth.Similar to developmental organoids, these . 11a), although there are notable exceptions. For example, bats live longer than expected for their body size. A relationship between developmental progression and ageing has also been found in studies of the epigenetic clock. Temporal epigenetic changes in developmental GRNs are sufficient to estimate an epigenetic clock for human, dog and mouse [The rate of ageing is also species-specific and results in the characteristic average lifespans for a species ,81. Curifigure 3nd mouse .Figure b). These findings are in agreement with the identification of protein stability as a regulator of developmental tempo and suggest that the rate of protein turnover tracks the course of time from fertilization to death. It would be interesting to test if perturbations that extend the lifespan  also slow developmental tempo. Understanding the mechanisms behind developmental tempo may shed light on the molecular mechanisms behind size and lifespan scaling.Moreover, recent research demonstrates that organisms with long lifespans generally have slower global protein turnover rates ,83 figub. These Highly abundant proteins in particular are more stable in long-lived animals . The inc. 12in vitro models of development. Studying tempo in developmental processes, aside from the phylotypic stage, and during tissue homeostasis, will address whether there are general mechanisms that track time during development and homeostasis and how changes in tempo are achieved.Biological clocks can be identified during development and homeostasis in processes that are evolutionarily conserved across species. Cell-autonomous mechanisms are starting to be deciphered thanks to the conservation of GRNs and the use of Moving beyond timers in single cells, three-dimensional models of development and homeostasis offer the potential to study the coordination of tempo at a tissue level. The development of comparable and robust protocols across species of organoids, and accurate dynamic measurements will be essential to gain insight into the dynamics of biological processes.Moreover, the identification of tempo mechanisms will allow us to investigate how to modulate the speed of progression. This will not only improve our understanding of biological processes but is likely to provide the means to engineer and refine methods to generate specific cell types for research and therapeutic applications.


Serious infection with respiratory syncytial virus (RSV) is associated with high risk in infants, children, and elderly. There is currently no approved vaccine against RSV infection, and the only available prevention is immunoprophylaxis utilized in high-risk infants, leaving the elderly without many options. In the elderly, the chronic low-grade inflammatory state of the body can play a significant role during infection. The cotton rat and mouse have emerged as the preferred small animal models to study RSV infection in the elderly. These animal models of aging have shown an age-dependent time course for clearance of virus correlating with a significantly diminished cytotoxic T lymphocyte and humoral immune response in old animals compared to adult animals. In addition, protection through vaccination is reduced in aging rodents. These results mirror the findings in humans. In mice and cotton rats, treatment with ibuprofen, a nonselective nonsteroidal anti-inflammatory drug (NSAID), to decrease the chronic low-grade inflammation of the elderly immune system has proven successful in restoring the function of cytotoxic lymphocytes. While more research is required, these treatment types promise a beneficial effect in addition to a putative vaccine. Choosing an appropriate animal model to study RSV infection in the aging immune system is essential to benefit the growing population of elderly in the world. This review focuses on the current research of RSV infection in the cotton rat and mouse as model systems for an aging immune system. Paramyxoviridae family, but was reclassified into the Pneumoviridae family in 2016 [Respiratory syncytial virus (RSV) is a nonsegmented negative sense enveloped RNA virus. RSV previously belonged to the  in 2016 . Disease in 2016 , 6. Beca in 2016 . The sin in 2016 . The treUnderstanding the aging immune response of the elderly is essential for the development of new therapeutics and vaccines. It has been shown that the aging of the immune response (immunosenescence) is characterized by reduction in antigen recognition and processing by dendritic cells and effector function of T cell subsets . It has Virus-induced damage and host response to RSV infection both contribute to the development of RSV disease, and age, which affects host immune status, is a major determinant of RSV disease severity and prognosis . In the Sigmodon hispidus) and mouse (Mus musculus) have been utilized as the preferred small animal models for investigating RSV infection in the elderly population [The selection of an animal model depends heavily upon the type of RSV disease being studied. There is no single animal model which replicates all aspects of primary RSV disease in the human adult or the at-risk subpopulations . The calpulation .The cotton rat and mouse have proven to be valuable animal models for studying RSV in the presence of an aging immune system. From the age of eighteen months and older, mice show significantly increased susceptibility to RSV infection, increased lung histology, and reduced immunity , 27–29, One of the biggest unresolved questions of RSV infection in the elderly is why the virus disproportionately affects this age group over others. In humans, it is known that clearance of RSV infection depends on the age of the infected individual . It is nAs the first line of defense against pathogens, the innate immune response is essential for the recruitment of immune cells to the site of infection. Key players of the innate immune response include natural killer cells, macrophages, neutrophils, and dendritic cells. Functions of macrophages, natural killer cells, neutrophils, and dendritic cells were reported to decline with age . A delayThe reduction in the frequency of naïve T cells together with the increasing proportion of terminally differentiated T lymphocytes have long been hallmarks of immune aging . Also, iWhile the importance of cytotoxic T lymphocytes during RSV infection has been shown, the humoral immune response can also play a key role in acute infection and protection against reinfection as well. In the aging body, the numbers of naïve B cells decrease and effector B cells accumulate leading to a reduction in the diversity of antibody responses . A loss One of the biggest hurdles of an aging immune system is vaccination. In humans, the reduced capacity of both innate and adaptive immune responses is thought to contribute to the decreased efficacy of vaccines in the elderly . Simply As the immune response to RSV infection in the elderly continues to be investigated, treatment options have emerged, while vaccines are still being developed. With the knowledge of the chronic low-grade inflammatory state of the elderly immune system, anti-inflammatory treatments have become increasingly popular. The use of antiviral  and anti-inflammatory (corticosteroid) treatments have been previously tested in adult, naïve cotton rats. Treatment with palivizumab alone leads to faster viral clearance, but little improvement in pulmonary lesions. By combining antiviral and anti-inflammatory drugs, reversal of pulmonary histopathology is caused by RSV, while, at the same time, overcoming the immunosuppressive effect of the glucocorticosteroid was achieved . With th2 (PGD2) which correlates with a progressive impairment in respiratory dendritic cells (rDC) migration to draining lymph nodes. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses (SARS-CoV and IAV-infected mice) [In mice, it was shown that there is an age-related increase in prostaglandin Ded mice) . Other ted mice) , 57. Theed mice) . With thed mice) . In thisIn a society where the aging population continues to grow, understanding the aging immune system is crucial. The cotton rat and mouse models have been invaluable in researching inflammation, adjuvants, and vaccines. Utilizing the cotton rat and mouse as animal models of the aging immune system during RSV infection has proven successful, while more research studies are necessary. Investigating new treatment options and testing vaccine candidates in these age appropriate models is essential to maintain the health of the growing population of elderly.


Loneliness and social isolation as antecedents of cognitive decline have received substantial attention in recent research. This symposium addresses this year’s conference theme of aging in the “new normal”. The COVID-19 pandemic has highlighted the negative impacts of loneliness and social isolation on older adults’ health and wellbeing. This symposium includes studies that shed light on the relationships between loneliness, social isolation and cognitive health using a multidisciplinary approach, and provide recommendations and future directions for advancing this research area. The first presentation examines cardiovascular biomarkers as potential mechanisms that mediate the longitudinal relationship between loneliness and cognitive decline with the HRS dataset. The second presentation examines several social isolation indicators and their effects on cognitive decline in a Canadian longitudinal study. Using the US ADRC longitudinal study of aging, the third study shows the effect of loneliness on cognitive health in older adults pre- and post-onset of the COVID-19 pandemic. The symposium concludes with a literature review of the different measures employed to operationalize the constructs of loneliness, isolation, which resulted in heterogeneous study findings on their influences on the risk of developing dementia. This review calls for consistent measures to produce comparable evidence on the health consequences of loneliness and isolation. In all, this symposium reports and reviews the latest evidence on the association between social isolation, loneliness and cognitive health amidst the ongoing COVID-19 pandemic. It also echoes the conference theme of transforming disruption to opportunities in aging health service and research.


Prehospitalization documentation is a challenging task and prone to loss of information, as paramedics operate under disruptive environments requiring their constant attention to the patients.The aim of this study is to develop a mobile platform for hands-free prehospitalization documentation to assist first responders in operational medical environments by aggregating all existing solutions for noise resiliency and domain adaptation.The platform was built to extract meaningful medical information from the real-time audio streaming at the point of injury and transmit complete documentation to a field hospital prior to patient arrival. To this end, the state-of-the-art automatic speech recognition (ASR) solutions with the following modular improvements were thoroughly explored: noise-resilient ASR, multi-style training, customized lexicon, and speech enhancement. The development of the platform was strictly guided by qualitative research and simulation-based evaluation to address the relevant challenges through progressive improvements at every process step of the end-to-end solution. The primary performance metrics included medical word error rate (WER) in machine-transcribed text output and an F1 score calculated by comparing the autogenerated documentation to manual documentation by physicians.P<.001).The total number of 15,139 individual words necessary for completing the documentation were identified from all conversations that occurred during the physician-supervised simulation drills. The baseline model presented a suboptimal performance with a WER of 69.85% and an F1 score of 0.611. The noise-resilient ASR, multi-style training, and customized lexicon improved the overall performance; the finalized platform achieved a medical WER of 33.3% and an F1 score of 0.81 when compared to manual documentation. The speech enhancement degraded performance with medical WER increased from 33.3% to 46.33% and the corresponding F1 score decreased from 0.81 to 0.78. All changes in performance were statistically significant (This study presented a fully functional mobile platform for hands-free prehospitalization documentation in operational medical environments and lessons learned from its implementation. Prehospitalization information provided by the first responders is often essential to subsequent treatment efforts including the accurate assessment of a patient, medical diagnosis, and rationale for treatment decisions in the emergency care settings. A patient record documented in the field promotes a continuum of care, playing a vital clinical role in the subsequent treatment of patients in emergency rooms, trauma centers, or other receiving facilities. Complete and effective documentation of prehospitalization care informs clinicians and staff of presenting vitals and symptoms, the initial assessment of the condition, attempted prehospitalization interventions, and observed response to the interventions -3. FailuThe US military has demonstrated an ongoing interest in potential technological approaches that enable efficient prehospitalization documentation at the point of injury in advance of a patient’s arrival to a field hospital -14. AdeqGiven the necessity of seeking solutions that will not degrade the clinical workflow, technology solutions using automatic speech recognition (ASR) have been explored for hands-free clinical documentation -23. A moASR consists of multiple components to convert input audio to output text. There are componentwise interventions known to address the listed challenges at a single component level. Recent studies demonstrated acoustic signal processing algorithms that offer improved resilience of ASR to background noise ,32. SomeDespite a number of available component-level interventions, it remains unknown how a combination of all these interventions simultaneously affects the overall performance of hands-free prehospitalization documentation in a noise-intensive operational environment. A technology approach encompassing all possible improvements at every process step of the end-to-end solution has the potential to make a substantial contribution to addressing similar challenges in the daily emergency and prehospital clinical practice.In this paper, we describe the design of our mobile platform for hands-free documentation in the operational medical environment and lessons learned from its use in a simulated environment. The purpose of the study is to perform a systematic evaluation of improvement opportunities for the platform by aggregating and assessing all possible component-level solutions at every process step. The platform was built to extract meaningful medical information from the real-time audio streaming and generate complete documentation before a patient arrives at a simulated field hospital. To this end, the state-of-the-art ASR solutions with relevant component interventions for modular improvement were thoroughly explored. Development of our platform was guided by qualitative research and structured evaluation to identify and address the relevant challenges through modular improvement at every process step of the end-to-end solution. Physician-supervised clinical simulation drills were conducted for the precise assessment of the system performance in the emergency settings.This research was approved by the Institutional Review Boards of Clemson University  and Palmetto Health System , with secondary review and approval by the US Army Medical Research and Material Command .Presimulation focus groups and follow-on simulation drill observations were used to assess medical workflow, scope medical information communicated, user requirements during operation, documentation needs, and overall design of platform. Six focus groups were held with 26 individuals across three categories of employment including emergency medical services, transport nurses, and emergency department physicians . Focus gThe overall system architecture design consisted of three major platforms: field mobile platform, field hospital platform, and headquarter back-end platform . The fieThe field mobile platform was designed to perform a basic preprocessing of audio captured at the point of injury for the hands-free prehospitalization documentation. The captured audio was converted into a transcript through the ASR module. The Tactical Combat Casualty Care (TCCC) card was selected as the standard format for prehospitalization documentation throughout the study; it has been well-documented that the complete TCCC documentation results in a higher casualty survival rate ,15. The The selection of each componentwise intervention was guided by relevant literature and a series of preliminary experiments . A hybriThe speech enhancement module was deployed based on Speech Enhancement Generative Adversarial Network (SEGAN), which enabled the rapid enhancement process without the need for explicit assumptions about the raw data and generalizability to various speakers and noise types . The modMulti-style training was adopted for additional noise resilience in the operational environment. In specific, ASR was trained with a noisy audio data set containing various types of battlefield noise. A total of 17 battlefield noise files were collected from Signal Processing Information Base . These nOur initial investigations showed the original language model was unable to detect medical and military terms used by the medical professionals during the simulation drills. The primary cause of the failure was that these terms were not present in the dictionary that was created from the original ASR training data. To address the issue, a new customized lexicon was trained from medical and military terms used in battlefield-related injuries and medical evacuation. First, the relevant medical and military fields were identified in the TCCC card, the most predominant documentation template of battlefield injuries. Using the Carnegie Mellon University Sphinx Knowledge Base Tool, a dictionary with these domain-specific words and their corresponding phonemes was generated to update the existing language model . The oriAlthough all of the aforementioned methods focused on the accurate transcription of conversation between patients and medics, additional processing extracting medical information from the machine-transcribed unstructured text was necessary for completing TCCC documentation. MetaMap is a key tool developed by the National Library of Medicine that has been widely used in biomedical information retrieval and data mining applications to obtain Unified Medical Language System Concept Unique Identifiers (CUIs) with corresponding textual descriptions . The posA total of three clinical simulation drills were conducted in 2017-2019 at Palmetto Health Simulation Center in Columbia, South Carolina. Each physician-supervised drill simulated a typical rescue mission in the medical operational environment. The scope of the simulation spanned from the battlefield to the field hospital, and thus, only the field and field hospital platforms were deployed during the drills. Three common battlefield injury types were used for the clinical scenarios: gunshot wound, amputation due to explosion, head trauma ,51. ThroEach simulation drill started in a room simulating the landscape of field and sky. Various types of battlefield noises were simulated in the room using multichannel high-output speakers. The medics treated patients as they would on a real battlefield during the first encounter. After the initial treatment, the patients were escorted to the flight paramedics waiting at the next meeting point. The patients were then transported to the next room simulating inside of a medical helicopter. Likewise, helicopter noises were simulated in the room using multichannel high-output speakers. After a certain amount of flight time, patients were then transported to an outdoor space where a field hospital had been set up. The patients received the basic examinations at the field hospital, which concluded one simulation drill. The same three clinical scenarios  were used for each simulation drill in turn. A total of 27 complete patient cases spanning from field to field hospital were simulated and collected, resulting in a total of 5.05 hours of audio recordings. The maximum noise level of 89 decibels was maintained for gunshot and helicopter noise when measured from the patient’s position.For qualitative evaluation, thematic analysis using a hybrid inductive and deductive approach was completed in Atlas.Ti 8 (Scientific Software Development GmbH) ,53. The A standard measure to evaluate ASR performance, word error rate (WER), was used to verify whether the acoustic and language models achieved performance comparable to the current state of the art. However, it was suboptimal to include all conversations captured throughout the drills measure since the main goal of our platform was adequate documentation of injuries rather than transcribing daily conversations. Thus, the primary evaluation measures relied on medical WER and referred to WER for only the sentences from medically oriented speech. For example, sentences from nonmedical conversations between the medics were not considered when evaluating the medical WER. The WER was calculated by comparing machine-transcribed text output and text transcribed by human medical transcriptionists who listened to the audio recording of all simulations. Another primary performance measure was based on the completeness of captured clinical information in the autogenerated TCCC documentation. The captured clinical information was assessed using the F1 score calculated by comparing the autogenerated documentation to the manual documentation by physicians. The cost-effect analysis to identify opportunities for modular improvement was based on how much more clinical information could be captured after each componentwise intervention. McNemar test with Bonferroni correction was used to detect the statistical significance of the improvement effect with respect to medical WER. A total of 4 settings with different combinations of modular improvements were tested using the selected measures. Additionally, one setting based on a commercial ASR solution was assessed using the same performance measures. Dragon Medical Practice Edition 4 (DMPE 4) software (Nuance Communications) is one of the predominant speech recognition solutions that assist clinicians with hands-free voice-dictated documentation in clinics. A setting with its ASR powered by DMPE 4 was compared with the settings with the different modular improvements .Four thematic areas include communication methods, communication content, device interaction, and information use . CommuniFocus group and simulation drill participants’ feedback emphasized the need for device flexibility and for the person wearing it to have control. They also encouraged the design team to make the device strong, durable, and lightweight. Simulation participants recommended that users would have to be trained to use the device and to talk aloud during care so that the device can capture what is being done. Finally, participants shared that short notes and recording that could replace charting would increase user perception of value and thus motivation to use. Physician providers noted that short notes or videos or photos of the injury or emergency site transmitted before patient arrival could be helpful.The total number of 15,139 words necessary for completing TCCC documentation were identified through transcription from audio recordings collected from all simulation drills. The field mobile platform equipped with baseline ASR achieved a medical WER of 69.9% with 10,582 word errors of 15,139 words . Multi-sAmong all the componentwise interventions, the combination of multi-style training and an updated language model resulted in the most improvement in medical WER; the error rate was reduced by 36.6% when compared to the baseline model. For specific examples of improvement made by the updated language model, see The previous studies on the extraction of medical information from the human-written clinical text have reported F1 scores ranging from 0.757 to 0.872, depending on a target entity to be recognized ,54. Our The observation made by the focus group identified considerable similarity between all patient transportation processes regardless of injury types. For example, all medical personnel described a similar set of information that is expected to share as they transition the patient from one setting to the next. The identified similarity between the processes enabled the labor-intensive closed domain solutions for the post natural language processing without concern for resource constraints . In our experience, both language model and medical information extraction could be further improved through rule-based or manual tasks such as observation-driven lexicon updates and preidentification of relevant CUIs for reducing false positives. The qualitative study to identify the similarity may provide the basis for cost-effect analysis to examine the feasibility of similar closed domain strategies.The importance of user training was pointed out during the focus group study. Accordingly, users were trained to turn on and off the system whenever appropriate, which could prevent the potential false positives incurred by nonclinic conversation. Next, the users were also trained to repeat the information whenever possible. It was observed that, if the same information is repeatedly spoken by a user, the system has a higher chance for complete documentation by properly capturing the information at least once, resulting in the improved high F1 score despite a relatively high WER. We have learned that the proper user training may result in performance improvement as significant as state-of-the-art componentwise interventions.The performance of the ASR module had a direct impact on the quality of the autogenerated documentation in our speech-to-patient-record application. It was observed that improvement in medical WER after each componentwise intervention is likely to improve autogenerated documentation quality evaluated by the F1 score. As expected, more medical word errors in ASR-transcribed text interfered with the post–natural language processing to extract medical information for documentation. A preliminary observation on the autogenerated documentation revealed that missing words in ASR output and incorrect negation due to word errors were the major causes of false negatives and positives, respectively.To some extent, our mobile platform resembles a personal artificial intelligence assistant platform on the commercial market, as it listens to its user and executes desired actions . Although our platform could deploy the same types of componentwise interventions known to be effective for the commercial platforms, not all interventions were effective in our application. In the context of everyday life, the personal assistance platform can benefit from speech enhancement that emphasizes the speech of the primary speaker  while suppressing the speech of secondary speakers. However, in the context of medicine, the same speech enhancement module may cause a higher medical WER by filtering out the patient’s response to doctors or speech from other care providers attempting to deliver information to the primary speaker. Our experience of the performance degradation reveals a necessity for more context-sensitive training for speech enhancement modules to enhance speech from both primary and secondary speakers in the emergency care settings.Our field mobile platform used only verbal communications for the documentation. As documented in qualitative study findings, information extraction from nonverbal communication along with the verbal communication is essential to reducing the loss of information. Future research may incorporate the existing computer vision solutions to examine if additional information can be extracted from nonverbal communication for more resilient documentation. In response to lesson 2, future studies are warranted to perform a hypothesis-driven study to assess the effect of user training on the resilience of documentation. Lastly, our platform was designed for the closed domain application exclusively for the three most common injury types on the battlefield. Although our study demonstrated that the closed domain strategy can be developed to significantly improve speech recognition performance for the target medical conditions, future speech-to-text and medical information extraction modules may explore to expand the platform design for more variety of medical conditions.To the best of our knowledge, this was the first attempt to create a fully functional platform for hands-free prehospitalization documentation in operational medical environments. Our application contributes to the body of existing knowledge for the development and assessment of platforms to enable hands-free clinical documentation in real-world noisy environments. The development of our platform was strictly guided by domain experts and a series of structured evaluations to examine modular improvement at every process step of the end-to-end solution. The lessons learned suggest potential refinements in the future endeavors to develop other similar platforms for speech-to-patient-record application.


Background: The aim of this systematic review is to analyze the available literature on the introduction of allergenic foods and gluten among preterm infants. Methods: A systematic review of published studies concerning the introduction of gluten and allergenic foods in preterm infants was performed on PubMed and on the Cochrane Library. Results: Of the 174 PubMed results, 15 papers were considered suitable for the review. A total of 83 records were identified through the Cochrane Library search; eight papers were included in the review. Additional papers were identified from the reference lists of included studies. A secondary search was conducted on the same databases to find recommendations and advice regarding healthy full-term infants that could be translated to preterm infants. Therefore, 59 additional papers were included in the review. Conclusions: Current guidelines for the introduction of solid food cannot be directly transposed to preterm infants. Further research is needed to provide evidence-based guidelines regarding weaning in preterm infants. To date, we can suggest that in preterm infants allergenic foods and gluten may be introduced when complementary feeding is started, any time after 4 months of corrected age, avoiding delayed introduction and irrespective of infants’ relative risk of developing allergy. Avoiding large amounts of gluten during the first few weeks after gluten introduction and during infancy is advised, despite limited evidence to support this recommendation. The period of complementary feeding (CF) represents a significant part of the 1000-day critical window [There are no guidelines available regarding the age of initiation of CF in preterm infants (<37 weeks gestation) who are at risk of altered postnatal growth ,3. In 19None of the scientific societies working on nutrition in infancy, including the European Society of Pediatric Gastroenterology and Nutrition (ESPGHAN), AAP or the Canadian Pediatric Society (CPS), indicate the time of introduction of CF for preterm infants . The lacThe introduction of allergenic foods and gluten has always been considered a challenge of CF in healthy full-term infants. In preterm infants, this is an issue of great concern. Given the absence of specific guidelines at present, the purpose of this paper is to review the available literature concerning the introduction of allergenic foods and gluten among preterm infants.A systematic review of published studies regarding the introduction of gluten and allergenic foods in preterm infants was performed. No limitation regarding year of publication was applied. http://www.ncbi.nlm.nih.gov/pubmed/, accessed on 1 March 2021) and the Cochrane Library . Recommendations, reviews, study protocols for reviews and trials published up to 1 March 2021 were eligible.The following databases were searched: PubMed . Of the potentially relevant studies, the integral papers were gathered. Their eligibility for inclusion was independently evaluated by two reviewers (F.Ch. and E.M.).Of the 174 PubMed results, 15 papers were deemed relevant for the review ,25,26,27Searching through the reference lists of the included studies, other papers were also selected. Given the shortage of available literature regarding the introduction of allergenic foods and gluten in preterm infants, the search was extended to include papers on this same issue in full-term infants. This additional search was carried out on PubMed and the Cochrane Library: 64 papers were selected and included in the review ,85,86,87The main characteristics of the included studies are reported in This review aimed to analyze the literature for data to provide specific recommendations for the preterm infant concerning the introduction of allergenic foods and gluten among preterm infants.We found a paucity of quality studies aimed at preterm infants and decided to supplement our search with results from studies and guidelines for term infants. However, these data should be used with caution as the preterm infant is not fully comparable to the term infant, even when corrected for age. Intestinal motility and permeability, hormonal and immune systems and the microbiome of the preterm infant are different. All this makes it essential and urgent to continue research in this direction.Preterm infants were considered to be at higher risk of developing food allergies due to increased gut permeability , increasLow levels of antibodies to cow’s milk and gliadin were found in preterm infants ,47. A laSome studies proposed that preterm infants are at increased risk of allergies ,5, notabThe most common pediatric food allergies are reactions to cow’s milk, hen’s egg, soy, peanuts, tree nuts, wheat, fish and shellfish. Although the majority of children with milk or egg allergies will become tolerant, few are at risk of developing atopic disorders or respiratory allergic diseases . Over thAs a result, the European Society of Pediatric Allergy and Clinical Immunology (EAACI) and the ESPGHAN have produced joint guidelines .In 2014 the EAACI Guidelines were released, providing evidence-based recommendations for primary prevention of food allergies . The AAPIn 2016, a systematic review and meta-analysis by Ierodiakonou  showed tThese data conflict with previous recommendations to delay the introduction of allergenic foods to the infant’s diet and suggests that current guidelines may need to be revised ,58,59. TA systematic review of 14 studies by Larson  has put In light of these discoveries and having reviewed the available evidence, in 2017, the ESPGHAN CoN provided new recommendations for the introduction of CF .The formulation of distinct recommendations for breastfed and formula-fed infants is not advisable. In a recent review, Agostoni et al.  found noIn February 2021, the update of the 2014 EAACI guideline was published , based oEczema is considered the highest risk factor for developing IgE-mediated food allergy; however, children without risk factors still develop food allergy . GuidancOther allergens should be introduced around 6 months but not before 4 months as well. During introduction of CF, infants should be fed a diverse diet in order to help foster prevention of food allergy . The 2021 EAACI guidelines try to answer the questions on the optimal timing and doses of food allergens that should be used to induce tolerance . HoweverCeliac disease (CD) is a chronic, multi-organ autoimmune disease that affects the small bowel in genetically predisposed persons precipitated by the ingestion of gluten. Based on analysis of the Norwegian MoBa cohort, the development of CD in children is not associated with intrauterine growth .Prevention of the occurrence of CD with infant feeding practices has been extensively discussed. In 2008, the ESPGHAN CoN recommended avoiding both early (<4 months of age) and late (>7 months of age) gluten introduction. It also recommended introducing gluten while breastfeeding . A recenTwo recent RCTs ,64 and tBreastfeeding had no preventive effect on the development of CDA or CD during childhood according to the systematic review by Szajewska . Only liDespite the negative results of studies testing different strategies of the timing of gluten introduction, a high quantity of gluten remains a suggested risk factor . Higher Even though breastfeeding should be encouraged for its well-known health benefits, neither any breastfeeding nor breastfeeding during gluten introduction has been demonstrated to influence the risk of CD ,75. IntrGluten may be introduced into the infant’s diet anytime between 4 and 12 months of age. The age of gluten introduction in infants in this age range does not seem to influence the absolute risk of developing CDA or CD during childhood . There iESPGHAN currently recommends avoiding large doses of gluten soon after its introduction and during infancy , despiteNo recommendation was made on gluten introduction in children from families with first-degree relatives with CD . The verIt is well known that in children with no genetic predisposition for CD, the timing and mode of gluten introduction do not influence the risk. Though the recommendations are only valuable to genetically predisposed infants because they are the only ones at risk of developing CD after gluten introduction, the protocol must be applied to all infants, given that genetic risk alleles are generally not known at the time of introduction of CF ,69. AdviThe introduction of allergenic food and gluten is a major concern of CF. As we reported, the loss of gluten tolerance is a dynamic process; neither breastfeeding nor the delayed introduction are effective in preventing the later development of CD. Concerning food allergy prevention, the current paradigm is shifting from avoidance to controlled exposure, with increasing amounts of evidence to support the early introduction of potentially allergenic foods to aid in the development of oral tolerance.To date, there is a severe shortage of evidence-based recommendations regarding CF in preterm infants , with CFIn light of the strict interrelationship between early nutrition and long-term health, specific recommendations on the optimal timing and strategy of complementary food introduction in preterm infants are needed, with a special focus on their specific nutritional requirements. Given the contrasting reports, RCTs specifically designed to assess the benefits and the risks of the age when and the way in which CF is started in preterm infants are needed . Some RC−“Highly allergenic” foods and gluten should be introduced during CF, after 4 months of corrected age, irrespective of infants’ relative risk of developing allergy. It is not recommended to delay or avoid such foods. −Large amount of gluten are to be avoided soon after its introduction and during infancy, despite limited evidence to support this recommendation.Having reviewed the literature and given the available evidence, our conclusions and recommendations regarding CF in preterm infants are that:These conclusions are summarized in Further research is needed to provide evidence-based guidelines regarding weaning preterm infants.


Peroneal nerve injuries results in tibialis anterior (TA) muscle paralysis. TA paralysis could cause “foot drop,” a disabling condition that can make walking difficult. As current treatment methods result in poor functional recovery, novel treatment approaches need to be studied. The aim of this study was to explore anatomical feasibility of limb reinnervation with our recently developed nerve-muscle-endplate grafting (NMEG) in the native motor zone (NMZ).  As the NMEG-NMZ technique involves in nerves and motor endplates (MEPs), the nerve supply patterns and locations of the MEP bands within the gastrocnemius (GM) and TA muscles of rats were investigated using Sihler's stain and whole-mount acetylcholinesterase (AChE) staining, respectively. Five adult rats underwent TA nerve transaction. The denervated TA was reinnervated by transferring an NMEG pedicle from the ipsilateral lateral GM. At the end of a 3-month recovery period, maximal muscle force was measured to document functional recovery.  The results showed that the TA was innervated by the deep peroneal nerve. A single MEP band was located obliquely in the middle of the TA. The GM was composed of two neuromuscular compartments, lateral (GM-l) and medial (GM-m), each of which was innervated by a separate nerve branch derived from the tibial nerve and had a vertically positioned MEP band. The locations of MEP bands in the GM and TA muscles and nerve supply patterns demonstrated that an NMEG pedicle can be harvested from the GM-l and implanted into the NMZ within the TA muscle. The NMEG-NMZ pilot study showed that this technique resulted in optimal muscle force recovery.  NMEG-NMZ surgery is feasible for limb reinnervation. Specifically, the denervated TA caused by peroneal nerve injuries can be reinnervated with a NMEG from the GM-l. Peripheral nerve injuries (PNIs) to the extremities and resultant muscle paralysis are a major source of chronic disabilities which limit the opportunities to work and diminish quality of life . AlthougWe developed a novel surgical technique called the nerve-muscle-endplate grafting (NMEG) technique for muscle reinnervation . The ideThe purpose of this study was to determine the anatomical feasibility of transferring an NMEG from the gastrocnemius muscle (GM) to reinnervate the ipsilateral denervated tibialis anterior (TA) muscle in a rat model.Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health .In this study, ten hind limbs of adult female Sprague Dawley rats  were obtained after completion of other experiments. The nerve supply patterns and the locations of MEP bands in the GM and TA muscles were studied. In addition, five rats were used in our pilot study to determine the surgical feasibility and functional outcome. These animal studies were ethically reviewed and approved by the Institutional Animal Care and Use Committee prior to the onset of experiments. All animals were handled in accordance with the Five fresh left legs of rats were removed and processed with Sihler's stain, a whole-mount nerve staining technique, to map out branching and distribution patterns of the sciatic nerve and its branches. The details regarding Shiner's stain have been given in our previous publications , 18. In Five entire GM and TA muscles on the left side were removed from rat legs. The muscles were treated with whole-mount AChE staining to locate the MEP band as described in our previous publications , 19. BriAfter determining the nerve supply patterns and the location of the MEP bands within the TA and GM muscles, we performed NMEG-NMZ surgery in five rats under general anesthesia as described in our previous publications , 16. FirThe TA is a fusiform muscle located in the anterior part of the leg. It arises from the lateral tibia, and its tendon inserts on the medial foot. Along with fibularis tertius, EDL and EHL, it comprises the anterior (extensor) compartment of the leg. TA lies medial to EDL, which makes it the most medial muscle in the anterior compartment of the leg.Sihler's stain Figures  and 2 shThe tibial nerve innerves the GM, soleus, FHL, FDL, and muscles in the foot . SpecifiThe MEP band is formed by numerous neuromuscular junctions. n = 5), the average muscle force of the reinnervated TA recovered up to 81% of the contralateral control. These findings suggest that if the TA is denervated following peroneal nerve injury, the NMEG-NMZ technique could be an option to treat “foot drop” caused by TA paralysis.The NMZs within the GM and TA muscles were delineated based on the locations of MEP bands and their innervating nerve terminals . Our NMEWe investigated the branching and distribution of the sciatic nerve and NMZs within the TA and GM muscles in the rat. This anatomical study on the nerve supply patterns and locations of MEP bands in the TA and GM muscles allows us to identify their NMZs for NMEG-NMZ surgery. Since the GM-l lies adjacent to the TA, an NMEG pedicle from the NMZ of the GM-l could reach to the NMZ of the TA without difficulty. Our pilot study showed that NMEG-NMZ resulted in promising functional recovery three months after limb muscle reinnervation.TA is the dorsiflexor of the foot and plays a critical role in walking. Paralysis of the TA caused by CP or DPN injuries or lesions results in foot drop, a disabling condition that can make walking difficult and lead to frequent falls.Traditional treatment modalities include use of an ankle-foot orthosis, tendon surgery, and nerve repair. Tendon transfer surgery is often used to treat foot drop with mixed results , 21. ForNerve repair , nerve gPoor motor recovery after PNIs and nerve repair is due primarily to insufficient axonal regeneration and failure to reinnervate the denervated MEPs in the target muscle. In response to this, we developed the NMEG. NMEG-NMZ is a recently developed novel surgical technique that targets NMZ for rapid MEP reinnervation, thereby leading to favorable functional recovery. Transplanting an NMEG from GM-l to the NMZ of the TA muscle is anatomically and surgically feasible and could offer several advantages to current treatment options. First, NMEG-NMZ provides an abundant source of nerve terminals that favor axonal regeneration. Second, as an NMEG pedicle is implanted directly to the MEP zone, NMEG-NMZ physically shortens regeneration distances and favors rapid axon-MEP connections. Finally, NMEG has ample pedicle-recipient muscle interfaces, which provide enough space for axonal regeneration at multiple points in the implanted NMEG pedicle and grow across the interfaces to reach the target.This study showed that transferring an NMEG pedicle from GM-l to the NMZ of the TA can be used to treat TA paralysis caused by CP or DPN injuries. Further experimental studies are needed to evaluate the efficacy of the NMEG-NMZ technique for limb muscle reinnervation.


Dear Editor,The increase in migration across countries has led to a range of problems in public health, border control, traveller and deceased identification, age assessment on unaccompanied minors, and identification of dead migrants. A review of these procedures in Italy highlights the need for a wider and centralized collection of antemortem and postmortem data as of the quality of postmortem data collection .Non-European Union (EU) nationals entering Europe are controlled by passports and fingerprints. Illegal migrants are without identification documents and for this reason they have to follow a specific legal path in order to issue proper identification documents, evaluate the juridical condition and the rights of undocumented migrants, as well as public health assessments. Migrants are taken to a hosting center where they are lodged until they are identified. They receive humanitarian assistance and health care during their stay at the hosting center, including general health evaluations, medical examinations, X-rays, blood chemistry tests, and microbiological analysis. Dentistry is not included in the general health evaluation, although dental care often seems to be requested by migrants (depending on their length of stay at the hosting centers).Age estimation of unaccompanied minors arriving at the borders of Italy is not performed using a national standardized protocol. Age estimation procedures can include physical examination, psycho-social interview and the wrist X-ray of the not writing hand. In some cases, dental age estimation methods are applied but are not systematically included in the assessment .Missing and unidentified dead migrants face further challenges. Standards in the forensic examination and postmortem collection are not sufficient to satisfy basic quality criteria for the management of the dead and their rights. As a result, the “Missing Migrants Project” estimates that there have been 17 124 migrant deaths and disappearances since 2014 and over 60% of these victims remain unidentified [Italy has the capacity of collecting identifying data respecting best practices in human identification and the human rights of the dead . Differedental fitness scores model suggested for military personnel by the North Atlantic Treaty Organization (NATO) agreement 2466 (STANAG2466) [The clinical evaluation of migrants at the EU border could follow the NAG2466)  and woulNAG2466)  and shouNAG2466) . The rigNAG2466) .Dental clinical assessment and dental assistance would allow the creation of migrant dental records, archived in a traditional database or in the health electronic record (EHR) of the patient which could be also integrated with a blockchain-based architecture and interoperable design when personal identification of a living or a dead migrant is required ,16. In sDental clinical assessment and dental assistance should be provided to migrants coming from developing countries when crossing border. Oral health care professionals could offer oral treatments of community dentistry on a voluntary basis. This would allow the creation of a national dental database, which may be disclosed to the authorities in case of crime investigations or identification. Forensic odontology should be methodological in all identifying procedures involved in border control and age estimation as in unidentified human remains. This would be achieved through community dentistry programmes and humanitarian forensic odontology organizations involved in human identification and human rights ,19.Emilio NuzzoleseDepartment of Sciences of Public Health and PediatricsUniversity of TurinTurin, Italyemilio.nuzzolese@unito.ithttp://orcid.org/0000-0001-9706-1106


Thoracic ultrasound is frequently used in the emergency department (ED) to determine the etiology of dyspnea, yet its use is not widespread in the prehospital setting. We sought to investigate the feasibility and diagnostic performance of paramedic acquisition and assessment of thoracic ultrasound images in the prehospital environment, specifically for the detection of B-lines in congestive heart failure (CHF).This was a prospective observational study of a convenience sample of adult patients with a chief complaint of dyspnea. Paramedics participated in a didactic and hands-on session instructing them how to use a portable ultrasound device. Paramedics assessed patients for the presence of B-lines. Sensitivity and specificity for the presence of bilateral B-lines and any B-lines were calculated based on discharge diagnosis. Clips archived to the ultrasound units were reviewed and paramedic interpretations were compared to expert sonologist interpretations.A total of 63 paramedics completed both didactic and hands-on training, and 22 performed ultrasounds in the field. There were 65 patients with B-line findings recorded and a discharge diagnosis for analysis. The presence of bilateral B-lines for diagnosis of CHF yielded a sensitivity of 80.0%  and specificity of 72.0% , while presence of any B-lines was 93.3% sensitive , and 50% specific  for CHF. Paramedics archived 117 ultrasound clips of which 63% were determined to be adequate for interpretation. Comparison of paramedic and expert sonologist interpretation of images showed good inter-rater agreement for detection of any B-lines .This observational pilot study suggests that prehospital lung ultrasound for B-lines may aid in identifying or excluding CHF as a cause of dyspnea. The presence of bilateral B-lines as determined by paramedics is reasonably sensitive and specific for the diagnosis of CHF and pulmonary edema, while the absence of B lines is likely to exclude significant decompensated heart failure. The study was limited by being a convenience sample and highlighted some of the difficulties related to prehospital research. Larger funded trials will be needed to provide more definitive data. Shortness of breath is responsible for more than 10% of non-traumatic emergency medical service (EMS) transports.3Prehospital medications have been associated with improved survival in patients with decompensated CHF, while increased mortality is associated with misdiagnosis.9In this study we sought to investigate the feasibility of training paramedics in acquisition and assessment of thoracic ultrasound images in the prehospital environment. The primary aim was to determine whether assessment of B-lines by paramedics in the prehospital setting could identify patients ultimately diagnosed with pulmonary edema from decompensated heart failure. We also sought to determine accuracy of B-line interpretation based on image capture and/or expert determination of B-lines when this was available.This was a prospective observational study of a convenience sample of patients being transported by emergency medical services (EMS) with a chief complaint of dyspnea. Patients were enrolled when a trained paramedic was working and had access to one of the shared portable ultrasound units. Paramedics were instructed to enroll as many eligible patients as possible.Participating paramedics were employed by American Medical Response (AMR) or local fire department-based EMS services and transported patients to two EDs located in New Haven, CT. Each EMS agency or fire department was given two or three portable ultrasound units. Enrolled paramedics participated in a 90-minute didactic training session, which included instruction in the use of a portable, handheld ultrasound device, the Vscan with Dual Probe , and basic principles of ultrasound, techniques to obtain the necessary thoracic views, as well as review of normal and pathologic video clips. They completed an identical, nine-question multiple-choice pre- and post-test during the didactic session.What do we already know about this issue?Thoracic ultrasound is frequently used in the emergency department (ED) to determine the etiology of dyspnea, yet its use is not widespread in the prehospital setting.What was the research question?Can paramedics use ultrasound to identify B-lines in patients ultimately diagnosed with decompensated heart failure?What was the major finding of the study?The presence of bilateral B-lines determined by paramedics is reasonably sensitive and specific for the diagnosis of pulmonary edema.How does this improve population health?The early diagnosis of pulmonary edema from decompensated heart failure should allow for more rapid initiation of pathology specific treatments.Paramedics then completed a 2–3 hour supervised hands-on session using the portable ultrasound device in the ED, imaging patients presenting with shortness of breath. The goal of this training session was to perform and interpret normal and abnormal scans on patients similar to those they could encounter in the field. During the hands-on sessions, paramedics were expected to correctly identify positive or negative findings in at least six patients presenting with undifferentiated pathology, based on previous competency studies with novice sonographers.Patients were eligible for inclusion in the study if they were aged >18 with the chief complaint of shortness of breath, and at least one of the following signs or symptoms of respiratory distress:Respiratory rate > 20 per minuteOxygen saturation < 92%Rales, rhonchi, or wheezing on pulmonary auscultationIncreased work of breathing: accessory muscle use, tripoding, nasal flaring.Reported progression of pedal edema or orthopnea.Permission to perform the ultrasound in the field was obtained by the paramedics using a scripted, brief verbal consent, with full consent obtained by one of the study investigators via telephone during the patient-medic interaction. This study was approved by the investigational review board of Yale University and the Yale-New Haven Hospital Center. Patients were enrolled over a 20-month period at the discretion of the participating paramedics in a convenience sample based on ultrasound device availability and patient volume.All prehospital ultrasounds were performed by paramedics using a GE Vscan with Dual Probe. In some cases, EMS physicians were present during EMS transport; however, they were specifically instructed not to influence or aid in ultrasound acquisition and interpretation. Paramedics assessed for B-lines with the phased array probe in the second or third intercostal space in the midclavicular line of the right followed by the left anterior chest. Paramedics were provided with standardized data sheets where they noted the presence of any B-lines (1–3) or significant B-lines . They were specifically instructed not to alter patient care based on their ultrasound findings, nor to delay standard care to perform the ultrasound. Paramedics were asked to record a clip from each ultrasound view on the device’s removable disk and note the time and date of the ultrasound on the data sheet, so that these images could be matched to the patient for review.At the conclusion of the study patient charts were reviewed for discharge diagnosis by a single investigator (JS) who was blinded to paramedic ultrasound findings and categorized the discharge diagnosis into CHF/pulmonary edema, chronic obstructive pulmonary disease/asthma, pneumonia, or other. Available images were collected from the ultrasound devices and matched to patient data sheets based on the image timestamps and the times recorded by the paramedic. These video clips were reviewed by an emergency physician (CB) with ultrasound fellowship training (defined as the “expert sonologist”) for adequacy of image acquisition and interpretation. Clips that did not definitively visualize the pleural line were deemed inadequate.We calculated sensitivity and specificity for the presence of bilateral B-lines and any B-lines with 95% confidence intervals (CI) based on discharge diagnosis. Paramedic interpretations were compared to expert sonologist interpretations using an unweighted Cohen kappa statistic.A total of 71 paramedics were enrolled and completed the didactic training. Of these participants, 60 reported no prior ultrasound experience and 11 reported prior ultrasound experience with an average of two estimated total hours using ultrasound before attending the training session. The average pretest score was 76.9%, and the average post-test score was 95.8%. After the didactic training, 63 paramedics completed hands-on training and 22 paramedics performed study ultrasounds in the field.Initially 69 patients were enrolled in the study; three were excluded due to insufficient identifying information. Paramedics recorded their assessments for the presence or absence B-lines in 65 patients. Patient demographics and clinical characteristics are summarized in Pulmonary edema or CHF was diagnosed in 15 of 65 subjects (23.1%), with any B-lines present in 14 and bilateral B-lines present in 12 subjects . The preParamedics recorded 117 clips from 33 patients on the hand-held ultrasound units; of those images, 63% were adequate for interpretation. Comparison of paramedic and expert sonologist interpretations of archived images showed good inter-rater agreement for detection of any B-lines .This is the first study we are aware of to assess the feasibility and utility of training paramedics in prehospital ultrasound for the diagnosis of CHF in the United States EMS system and the first to use an ultra-mobile device. These results show that the presence of bilateral B-lines as determined by EMS is reasonably sensitive and specific for the diagnosis of CHF, while the absence of any B-lines makes the diagnosis unlikely. A previous study in Denmark examining assessment for B-lines in CHF using a larger laptop-sized device (SonoSite Edge) enrolled 40 patients and found a sensitivity of 94% for B-lines in the diagnosis of CHF, concluding that ultrasound could be helpful in excluding CHF, which is consistent with these results.11Another study of prehospital, thoracic ultrasound in medical patients with respiratory distress found that paramedic-performed pulmonary ultrasound with remote physician interpretation did not meet the authors’ predefined standards for feasibility.While we believe that this study adds to evidence that motivated prehospital providers can be trained to perform and obtain useful information that can potentially impact treatment and patient outcome, conclusions regarding feasibility need to be tempered by the inconsistent use of ultrasound in this setting. While 63 paramedics completed training, only 22 ultimately enrolled subjects, and our overall enrollment was lower than expected given the duration of the study. Further study is needed to identify the barriers to ultrasound performance in this setting and to understand how EMS providers may be more incentivized to incorporate ultrasound into their practice.The implementation of ultrasound into an EMS system requires a significant initial monetary investment, instructor and paramedic time dedicated to training, and ongoing oversight of user performance for patient safety. Additional study is necessary to determine whether paramedic detection of thoracic pathology can lead to meaningful changes in management that would justify these costs. It seems probable that earlier diagnosis and initiation of pathology-specific treatments would positively impact patient care, although this was outside the scope of our study. Many of these challenges and costs of implementing ultrasound usage are likely to decrease in the future as portable units become more affordable and widespread ultrasound proficiency among graduating emergency physicians increases the availability of instructors.This study was limited by relatively low paramedic participation, low enrollment of eligible patients, logistic challenges of retrieving and sharing units, and difficulty recording data and ultrasound images. Prehospital patient care research is consistently challenging for clinicians, and this study was no exception.We are unable to confidently suggest that paramedics retained thoracic ultrasound skills following their training or routinely used them in their patient evaluations. In discussions with participating EMS providers, most felt that ultrasound was useful but noted that difficulty adhering to study protocols, data collection requiring manual input, and limited ultrasound device availability were significant challenges. User interfaces that facilitate input of patient information, documentation of findings, image archival, and submission for review would almost certainly increase the quantity and quality of data collected in futures studies. Additional research focusing on paramedics’ attitudes regarding the utility of ultrasound would also be advantageous in determining how to implement sustained use in prehospital practice patterns.Average transport times for most patients in our system are less than 10 minutes, rendering ultrasound study completion and full documentation of findings difficult. These short transport times might have also biased paramedics to enroll less-ill patients requiring fewer interventions affording the paramedics the time necessary to perform the ultrasound. Ultrasound may have greater utility in prehospital systems with longer transport times, where paramedics are engaged in prolonged patient management, and misdiagnosis leading to inappropriate treatments is more detrimental. As enrollment was determined by the paramedics, it is possible that there was bias toward selecting patients with a clear diagnosis of CHF or pulmonary edema. In this study, 23% of patients were discharged with a diagnosis of CHF, which is slightly higher than the rate of 16% previously cited in studies of patients presenting to EMS with shortness of breath.1Of the clips archived, 37% were inadequate for interpretation. This suggests that obtaining adequate images in the prehospital setting may be difficult for novice, non-physician sonographers. This may be partially ascribed to the paramedics’ training sessions, which focused primarily on scanning technique, normal findings, and pathology, with less emphasis on the adequacy of images and the importance of archiving for review. On several occasions inadequate images were submitted alongside adequate images for the same patient; it is possible that some of the inadequate images were recorded inadvertently by the paramedics. Ideally, ultrasound units used in the prehospital setting would allow for wireless transmission of images to an archiving system with the capability to include ultrasound interpretations for review. Compliance with image archival protocol would also be improved by user interface restrictions that discourage ultrasound use without entering patient identifiers or saving clips.Among the logistical challenges of prehospital ultrasound are device fragility, need for charging, and the requirement for physical or wireless connectivity. Advances in portable ultrasound units since the start of this study (including the second-generation Vscan Extend) have already resulted in devices that are more amenable to prehospital use. Many of these devices allow for remote video guidance in scanning technique and image acquisition in real time by a more experienced clinician who is not at the bedside. The advent of capacitive micromachined ultrasonic transducer-based probes may also alleviate some of these issues. Production of these probes is cheaper than their piezoelectric counterparts, making them more easily obtainable for research purposes and affordable for EMS agencies.This observational pilot study suggests that prehospital lung ultrasound for B-lines may aid in identifying or excluding CHF as a cause of dyspnea. The presence of bilateral B-lines as determined by EMS is reasonably sensitive and specific for the diagnosis of CHF and pulmonary edema, while the absence of B-lines is likely to exclude significant decompensated heart failure. The study was limited by being a convenience sample and highlighted some of the difficulties related to prehospital research. Larger funded trials will be needed to provide more definitive data.


Objective: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity. Multiple cognitive training appeared to be more effective than working memory training, but the evidence remains insufficient, particularly for the subgroup symptoms and executive function behaviors at home. Further analysis of the impact of factors on the effectiveness would facilitate the development of cognitive training.Methods: We searched PubMed, Cochrane Library, Psyche, Embase, Chinese Biomedical Literature Database, CNKI, and Weifang Database, and included randomized controlled trials (RCTs) of children with ADHD undergoing cognitive intervention. Metaanalysis and univariate metaregression were performed by STATE. The risk of bias was assessed with the Cochrane risk of bias tool 2.0 by the two investigators separately. This study was registered with INPLASY, number INPLASY202140065.Results: We included 17 RCTs in the systematic review, with a combined 1,075 participants. For metaanalyses of both subgroups of ADHD symptoms and the executive function behaviors, the test of published bias failed to reach the p < 0.05 level. When all of the training are considered together, cognitive training can improve the presentation of inattention symptoms  and executive function behaviors ]. In the subgroup analysis, the effects of working memory training on both presentations were not statistically significant. In contrast, the multiple cognitive training had significant effects on the presentation of inattention symptoms , hyperactivity/impulsivity , and the executive function behaviors . In addition, metaregression analysis showed that only training frequency did significantly impact the symptoms of ADHD and the executive function behaviors.Conclusion: This study showed that improvements in symptoms and executive function behaviors were related to the domains of cognitive intervention. The findings suggest that multiple domains of cognitive training and moderate training frequency may have wider clinical benefits. All the above results highlight further research in refining the executive functions of children with ADHD and developing individually tailored cognitive intervention on homes based for children with vulnerable executive functions.Systematic Review Registration: [http://inplasy.com/], [INPLASY202140065]. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity . The impWith the extensive body of research into the etiology and pathophysiology of neurodevelopmental disorders, such as ADHD and autism, more neuropsychological mechanisms could predict behavioral performance and support the design of non-pharmacological therapies . Many stThe aim of this metaanalysis and systematic review was to assess the effect of cognitive intervention on symptoms and executive function behaviors of children with ADHD.Selection criteria were identified according to the PICO principle. Studies were included if they conformed to the following inclusion and exclusion criteria. The intervention consisted of cognitive training or executive function training targeting domains of neuropsychological deficit . The control conditions were treated as usual, waiting list, active/placebo/sham  activities, or alternative training programs. Outcomes included the presentation of ADHD symptoms (inattentive and hyperactive/impulsive symptoms) and parent ratings of executive function behaviors . The BRIEF includes global executive composite (GEC) index, behavioral regulation index (BRI), and metacognition index (MI), derived from eight general executive function subscales, exploiting the efficacy of gathering structured observations of executive functions in daily life environments . Study tEnglish literature databases  were systematically searched using predefined terms based on Sonuga-Barke et al. until August 2021. Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI), and SinoMed as Chinese databases were searched following the same strategy as the former. The following mesh terms were used: attention deficit disorder with hyperactivity, cognitive training, randomized controlled trial, and executive function training. Detailed information on the search strategy and syntax for each database is available in “p < 0.05. The I2 was calculated a posteriori to estimate between-trial SMD heterogeneity. Publication bias was assessed with funnel plots and Egger’s tests. Univariate residual maximum likelihood (REML)-based meta-regression analyses on presentation and behaviors were used to assess the effect of potential factors of training .Two review authors had independently extracted data using specially developed forms based on the clinical research elements. The risk of bias of included studies that were assessed with the Cochrane risk of bias tool 2.0 by two investigators separately, in terms of five domains of the Cochrane Collaborations tool: namely selection bias, performance bias, detection bias, attrition bias, and other bias. Any disagreement was again resolved by consensus with the senior authors. Data were exported to STATA Version 14 statistical software for analysis. The effect size was calculated using the random-effect model for each variable by the reported data . SMD was calculated as the mean of post-treatment in the intervention group minus the mean of post-treatment in the control group divided by the pooled pre-test standard deviation with a bias adjustment. Given the inherent heterogeneity of studies, the random effect model was used. To evaluate the possible sources of heterogeneity, subgroup analyses were conducted. When significant heterogeneity was observed, sensitivity analyses were performed. For all analyses, significance was determined by Seven trials used working memory training that involved computer-based programs ; one triThe first set of analyses examined the impact of cognitive training on the presentation of inattention and hyperactivity/impulsivity symptoms  for analysis of blinded measures.When analyses were restricted to outcomes reported by the parent, the effect size remained significant for inattention but not for hyperactivity/impulsivity. In subgroup analyses, trials of multiple cognitive training remained a significant effect size for inattention and hyperactivity/impulsivity symptoms. Despite the minor heterogeneity between trials of working memory training, the results have not yet shown significant benefits in any analysis. There was a lack of sufficient studies reported only by the parent  due to the more neuropsychological domains of executive function training involved. However, it is neither more frequent (2.94 per week) nor more sessions  than working memory training. It is interesting to note that in the metaregression analysis, we identified no significant effect of sessions and durations of cognitive training on any presentation of ADHD and the global executive composite of BRIEF. The most surprising aspect of the results is that training frequency significantly affects the SMD for each presentation.Compliance was measured as the proportion of adhering participants. There are 2 two hypotheses for the treatment adherence of multiple cognitive training in ADHD. One of the issues that emerge from training programs is complexity, and long-term due to multiple training tasks may weaken adherence. On the contrary, the second hypothesis assumes that multiple cognitive interventions can improve compliance because treatment can reduce the boredom and monotony of single-task training for children with ADHD. This review shows a slightly higher compliance percentage to multiple cognitive training than to working memory training in both the intervention and control groups. This observation may support the hypothesis that the variety of cognitive training components may improve adherence to treatment for children with ADHD. The study of psychological time as information shows that the reduction of time promotes an increase of boredom and the under-motivation state, sometimes associated with a general decrease of well-being reflecting on adaptive behaviors . These rSecondly, heterogeneity between cognitive training programs needs to be discussed. The finding that emerges from the subgroup analyses is that effects of multiple cognitive training have a higher level of homogeneity than working memory training. These findings suggest that a substantial part of the overall estimated cognitive training effect likely originates in the neuropsychologic heterogeneity of ADHD. Based on the previous work in this field, neurocognitive heterogeneity is gradually recognized as a pervasive phenomenon in ADHD . The resn = 6) that reported blind measurement. There were insufficient studies (n < 5) to analyze the effect of multiple cognitive training in blinded measures reported by parents. Therefore parents may have been affected by expectancy bias or the Hawthorne effect. Second, the use of a waitlist control group for participants who are more challenging to treat or who perceive the treatment as less beneficial may drop out of trials. However, the compliance was relatively reasonable in most trials. Third, it cannot be ignored that medications hold the first-line role in the treatment of ADHD. Exactly, many of the studies had inclusion criteria that allowed children with ADHD to maintain a well-adjusted and stable dose of medication intake, which reflected that cognitive training alone is less acceptable to children and guardians.Several limitations need to be discussed when interpreting the current results. First, these promising findings are tempered by the limited number of trials (On the other hand, most parents remain open to non-pharmacological interventions, as evidenced by the overall proportion of adherence. In terms of metaregression analysis, we found no significant effect of medication on both presentation and the global executive composite of BRIEF. This finding is similar to the prior metaanalysis of the cognitive training effect that remained unaltered when the analysis controlled the no or low medication trials . DespiteCognitive training is a non-invasive, safe, and inexpensive intervention that can be implemented quickly and conveniently in a home setting. This metaanalysis aimed to synthesize more areas of populations, multiple cognitive training exposures, and parent-rated outcomes to augment the ecological validity while maintaining the suitability of evidence. In summary, multiple cognitive training alleviates the presentation of inattention and improves general executive function behaviors in children with ADHD. Even though people in some areas are quarantined at home because of the pandemic, in a way telemedicine can reduce concerns about the absence of medication or adverse effects caused by reliance on medication. Working memory training was proven ineffective in some cases, but it cannot be ignored as an essential executive function in line with previous studies. We advocate that multiple cognitive training should be available to compensate for the well-proven executive functions in neuropsychological domains rather than repeating them in a single-task model. That may benefit children with ADHD to coordinate various cognitive functions. Further research is needed to confirm and extend these psychology fields.The original contributions presented in the study are included in the article/SC, JY, and JW contributed to the conception and design of the study. QZ and JZ screened the articles and extracted the data. JY performed the statistical analysis. SC wrote the first draft of the manuscript. JY and YZ wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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