Promoting evidence-based antibiotic prescribing through successful antimicrobial stewardship (AMS) programmes is critical to preserving the effectiveness of antibiotics for common infections in primary care. This requires a coordinated multidisciplinary effort. Such pharmacist–prescriber partnerships have been effective in high-income countries (HICs). Yet, evidence generated in such countries is not always applicable because of different social determinants of health.A multidisciplinary workshop was conducted with pharmacists and clinicians  on community-based antibiotic stewardship, the purpose of which was to explore how and where such partnerships might work in publicly funded primary care clinics in the greater Cape Metro region.Participants perceived that promoting effective AMS was a priority for South African primary healthcare. However, it was clear that there are many hurdles to overcome working in settings that are relatively resource-poor. Prescribing guidelines needed to be harmonised. Participants felt that staff training on the principles of AMS should be mandatory. Research was urgently needed to better understand their community’s understanding of antibiotic use and AMS, and to champion outreach projects in the community.Important stakeholder perspectives in the community were highlighted to promote a multidisciplinary approach to AMS initiatives in primary care. These will need to be addressed to optimise antibiotic prescribing in the community. Overprescribing and inappropriate prescribing of antibiotics are the principal modifiable drivers of antibiotic resistance.4 and practical steps to address the governance framework needed at each level of the health system.5 This will become increasingly important in the transition to the country’s anticipated National Health Insurance (NHI) where pharmacists are likely to expand their role for primary healthcare services to increase access.6South Africa has shown much progress with major shifts in policy towards combatting antibiotic resistance. The country has a blueprint for the steps to be taken by healthcare practitioners and others to enact antibiotic stewardship at all levels of healthcare7Pharmacists and clinicians are being increasingly engaged in antibiotic stewardship partnerships to improve clinicians’ antibiotic prescribing. Antibiotic stewardship programmes aim to promote evidence-based antibiotic prescribing and typically involve educational programmes, the implementation of evidence-based guidelines, and audit and feedback for prescribers.8 In primary care, a recent review showed that such partnerships can be effective in decreasing the antibiotic prescribing rate  and increasing guideline-adherent antibiotic prescribing .9 Included studies, however, were all conducted in high-income countries (HICs). None were conducted in Africa. Yet, evidence generated in HICs is not always applicable because of differences in the social determinants of health.10Although the ‘practitioner–pharmacist’ collaboration model exists, this is more commonly found in hospitals than in community-based primary care. In hospitals, pharmacists play an active role in improving the appropriateness of antibiotic prescribing practice through the provision of expert advice, education and training, liaison with regards to formulary, the provision of resistance data, raising awareness of guideline adherence and policy-guided antibiotic prescribing.We therefore set out to explore the feasibility of a pharmacist–prescriber network in publicly funded primary care facilities to optimise antibiotic prescribing by frontline clinicians. We specifically wanted to know how and where such pharmacist–prescriber interventions might work in primary care clinics in the greater Cape Metro region and to identify the opportunities and barriers of good stewardship at primary care facilities in the region.We advertised and ran a local AMS workshop, held in October 2019 in Bellville, Cape Town. We invited any practising frontline pharmacists, nurses involved in prescribing, and doctors working in Community Health Centres (CHCs) or Community Day Centres (CDCs). Health professionals working solely in hospitals were excluded. We did not pre-specify a participant’s level of seniority or experience, but rather took an inclusive ‘bottom-up’ approach, focussing on a participant’s unique perspective on prescribing at their CHC or CDC, and their potential to contribute meaningfully to the workshop.Participants were divided into smaller groups to facilitate a balanced discussion of four topics see  and thenBOX 1Group workshop questions on community antimicrobial stewardship.What stewardship strategies can be implemented at primary care facilities? Give examples.What are the barriers of stewardship at primary care level and how can they be overcome?What are the enablers of stewardship in primary care facilities?What social  and behavioural aspects should be addressed to advance stewardship?Source: Reproduced and adapted with permission from Professor Philip Howard, British Society for Antimicrobial Chemotherapy.We confirm that ethical clearance was not needed/required for this study.Thirty-three participants contributed to the workshop  see . ParticiThe participants valued the use of readily available local and national prescribing guidelines. However, they pointed out that there were often conflicting prescribing regimens. Local communication circulars were often at odds with guidelines and some clinics were using guidelines that had been superseded. There were also concerns raised that private pharmacists at the community pharmacy level were often overlooked in current AMS initiatives yet have an important role to play.Although a timely audit and feedback were important, participants thought that time constraints, poor record-keeping and inadequate dissemination to the entire team made them question the value of prescribing audits. Participants perceived that the attitudes of patients towards prudent antibiotic use was at times unhelpful. This was compounded by inadequate time to discuss a non-antibiotic strategy, provide relevant health promotion (e.g. hand hygiene) or safety-netting of antibiotic use. Participants acknowledged that strong local leadership and good clinical governance were key. They suggested that all patient-facing clinic staff in the community should be required to have standard training in AMS.Participants wanted all clinic staff to show a unified front in applying an evidence-based approach to antibiotic prescribing and build patient trust in healthcare facilities. Thus, research was urgently needed to better understand their community’s understanding of antibiotic use and AMS. They felt that community healthcare workers might be best placed to champion AMS outreach projects. They also wanted additional initiatives on how best to engage patients about antibiotic use through relevant promotional media and health campaigns tailored to the local community.This workshop provided critical perspectives from stakeholders in publicly funded healthcare facilities to promote a multidisciplinary approach to AMS initiatives in primary care. We found that despite the enormous hurdles to overcome in the public health sector, there was an awareness and collaborative spirit to make AMS a priority.www.fidssa.co.za/SAASP/Edu_Material). This should also be extended to those health professionals still in training and private community pharmacies.Clinically, our findings support the need for clinics to ensure that the latest prescribing guidelines are being used and to communicate this to all staff – for example, setting up a suitable information-sharing platform (work WhatsApp group). All staff need to demonstrate their competencies in AMS by completing freely available AMS training modules (e.g. For policymakers, local and national prescribing guidelines need to be congruent with each other. They should also consider developing guidelines for common infection syndromes where antibiotics might not provide any additional benefit. Engaging patients in the discussion about antibiotic use, its harms and benefits for common infection syndromes and so forth needs to be incorporated into future health campaigns, bringing relevant information to the local community. Patients should receive clear information, ideally reinforced with leaflets or text messages, about the likely duration of symptoms, self-care, and the likely benefits and harms of antibiotics.Future research should focus on establishing studies to prospectively collect antibiotic prescribing data in primary care. This would require novel collaborations between pharmacists and prescribers to collaborate and collect prescribing data and link these to clinical indications. Currently, these data are retrospective and not linked to clinical indications. This is a major evidence gap but essential to describe the problems experienced about access to, and excess of, antibiotics for acute infection syndromes. Such descriptive studies are key to informing larger trials that can support the improved use of antibiotics.Our multidisciplinary workshop raised important stakeholder perspectives on potential AMS initiatives in primary care. Strategies that can optimise antibiotics can help to provide consistency in healthcare delivery, reduce inequality in healthcare provision, and ensure the continued effectiveness of antibiotics for common infections.


Globicephala melas), and assess shifts in pilot whales and their prey relative to climate velocity in a rapidly warming region of the Northwest Atlantic. We found a poleward shift in pilot whale distribution that exceeded climate velocity and occurred at more than three times the rate of fish and invertebrate prey species. Fish and invertebrates shifted at rates equal to or slower than expected based on climate velocity, with more slowly shifting species moving to deeper waters. We suggest that traits such as mobility, diet specialization, and thermoregulatory strategy are central to understanding and anticipating range shifts. Our findings highlight the potential for trait-mediated climate shifts to decouple relationships between endothermic cetaceans and their ectothermic prey, which has important implications for marine food web dynamics and ecosystem stability.Climate change is redistributing biodiversity globally and distributional shifts have been found to follow local climate velocities. It is largely assumed that marine endotherms such as cetaceans might shift more slowly than ectotherms in response to warming and would primarily follow changes in prey, but distributional shifts in cetaceans are difficult to quantify. Here we use data from fisheries bycatch and strandings to examine changes in the distribution of long-finned pilot whales ( As a result of differences in thermoregulatory mechanisms and energetic expenditure when faced with changing environmental temperatures, climate change may have fundamentally different impacts on ectotherms and endotherms10. It is largely assumed that ectotherms will respond more quickly to warming than endotherms12. The physiological performance of marine ectotherms is a function of water temperature and thus warming has had marked and measurable impacts on their growth, population productivity, and spatial distribution15. In contrast, endotherms have a greater capacity to maintain a constant body temperature by altering metabolic heat production in response to temperature fluctuations, but physiological thermal limits still constrain spatial distribution at broad scales16.While shifts in distribution18. It is generally thought that species must keep up with the pace of climate change in order to survive17. However, there is some controversy as to the relative degree to which climate velocity versus species traits explain range shifts. In marine ecosystems, previous studies have found that species traits do not strongly influence a species’ response to climate velocity19 while others have found that species’ traits were key to explaining range shifts20. However, these studies focus on ectotherms. For endothermic marine predators, the relative importance of direct thermoregulatory responses vs. indirect effects mediated by prey dynamics in marine predators is critical to understanding how they may respond to climate change22. Since marine mammals are large and abundant endothermic predators with higher metabolic rates than ectotherms, their large prey requirements regulate marine foodwebs25 and differential climate responses between these predators and their ectothermic prey would have formidable impacts on the resilience and stability of marine ecosystems27. Thus, considering traits including thermoregulatory strategy is critical to understanding species range shifts across many taxa.Understanding the pace of climate change, or climate velocity, is key to understanding species responses in a given habitat28. Cetaceans spend their whole life underwater, and thus warming waters may be more likely to directly impact thermoregulation in cetaceans than other marine endotherms such as flying seabirds that are not constantly immersed in a highly conductive environment. While thermal tolerances of cetaceans are not well understood, in broad terms, different taxonomic groups of cetaceans are known to vary considerably in their thermal tolerances. Baleen whales undertake long annual migrations between high latitude feeding grounds and tropical breeding grounds and are adapted to occur in a wide range of temperatures29. Conversely, most odontocetes have more limited ranges and their morphology and physiology reflect adaptations to the thermal conditions in their range. For example, cooler water species typically have lower surface area to volume ratios in their body core, and blubber with a higher lipid content, lower conductivity, and increased fatty acid stratification31. The larger appendages of long-finned pilot whales in comparison to short-finned pilot whales may reflect the need for enhanced mechanisms of heat dissipation in the large, well-insulated long-finned species, which occurs in cooler waters32.For endotherms, the use of elevated metabolism to maintain a constant body temperature consumes a major part of the energetic budget at environmental temperatures above or below the thermoneutral zone34, resulting in range contractions for cool water species, poleward distributional shifts for temperate species, and range expansions for warm water species21. There is evidence that considerable distributional shifts have occurred in marine mammal species in recent decades, with changes in the occurrence of cool and warm water cetacean species occurring in association with warming waters38. However, our ability to quantify distributional shifts in marine mammals is limited by the lack of reliable time series of abundance and distribution for most species36.Distributions of many cetacean species are expected to move poleward under climate change40; at-sea sightings rates from line transect surveys used to assess abundance are low, necessitating high survey effort to produce abundance estimates41. Consistent, standardized surveys with sufficient temporal and spatial coverage to detect distributional shifts over decades are not typically feasible and standardized monitoring effort for cetaceans in US waters is likely insufficient for detecting trends in the abundance and distribution of cetacean populations41. Observations from stranding events and fisheries bycatch provide important means of revealing changes in cetacean distribution over time, and may sample cetacean diversity better than surveys of live animals42. Further, some marine mammal species are difficult to identify at sea, and strandings records and observations of fisheries bycatch by onboard observers allow species-specific trends to be examined for species which are otherwise difficult to identify.Measuring long-term changes in cetacean populations presents a considerable challenge for biologists and managersGlobicephala melas) relative to their fish and invertebrate prey over a 25-year period in the Northeast United States (NEUS). We use strandings and bycatch data to examine changes in the distribution of long-finned pilot whales, and analyze catch data from fisheries-independent trawl data to examine long-term trends in the distribution of four dominant prey species of long-finned pilot whales, long-finned squid , short-finned squid (Illex illecebrosus), Atlantic mackerel (Scomber scombrus), and Atlantic herring (Clupea harengus). We test the hypothesis that both predator and prey, which differ considerably in their species traits, will shift at the same rate relative to local climate velocity. We also examine rates of fisheries bycatch relative to SST for evidence of thermal limits to pilot whale distribution and test the assumption that the endothermic predator will shift more slowly or lag their ectothermic prey.Here, we examine changes in the distribution of the long-finned pilot whales , illustrating that while the spatial distribution of bottom trawls did not change, the temperature increased in the region where bottom trawls were conducted.The mean poleward distance of pilot whale observations increased linearly through time (Adjusted RScomber scombrus) and Atlantic herring (Clupea harengus), showed a significant poleward shift in distribution . Atlantic herring, longfin squid  and shortfin squid (Illex illecebrosus) showed significant shifts into deeper waters . Poleward shifts in Atlantic mackerel and Atlantic herring were associated with increasing SST, but long-finned pilot whales shifted poleward more than twice as rapidly as their prey in response to increasing SST  and higher than any rate reported for fishes and macroinvertebrates in this region4. The shifts in herring and mackerel in the last 25 years are greater than those assessed using data extending to the 1960s2 likely due to the rapid warming that occurred from 2003 to present46. Further, long-finned pilot whales shifted at a rate that was considerably higher than climate velocity within the NEUS, but fish and invertebrates shifted as expected or slower than expected based on climate velocity. Of the five study species, only 1 was found to be shifting at a rate reflective of climate velocity. Thus, we suggest that climate velocity alone is not sufficient for understanding the varied responses to warming in species that differ in key traits.Rather than lagging distributional shifts in their ectothermic prey, the observed rate of poleward movement in long-finned pilot whales is higher than shifts observed in the prey species observed in this study  in a matter of weeks48, and pilot whales do not have fixed breeding or feeding areas like some other marine mammals. The range of long-finned pilot whales in the Northwest Atlantic extends from the NEUS into the Labrador Sea, and higher rates of climate velocity were observed in more northerly waters of the Northwest Atlantic , and the vast majority of their time is spent in waters of less than 15 m depth; thus surface temperatures play a larger role in their thermal budget than might be expected for marine mammals that spend more time at depth55. In contrast, fish and invertebrates occur throughout the water column and can shift poleward, offshore and/or deeper in order to stay within their preferred temperature ranges57. Distributional shifts in fish and macroinvertebrates in this region are generally more strongly associated with bottom rather than surface temperatures59 and bottom temperatures are also warming at a slightly slower rate than surface waters in this region60. Our results suggest that these species may be compensating for warming by shifting to deeper depths rather than shifting to more northern waters. Similarly, Pinsky et al.4 found that in regions of increasing SST, fish assemblages tended to shift deeper to avoid warming waters. However, the bottom trawl data that we examined do not fully capture the distribution of prey species in the water column and the relative importance of poleward shifts and shifts in depth merit further attention.The ability of fish and squid to move to cooler waters by moving deeper in the water column likely plays an important role in the observed mismatch in climate responses between pilot whales and their prey. Long-finned pilot whales are deep diving species that can dive to depths of more than 800 mThe shift in distribution of marine fishes can also partially be attributed to changes in population productivity with populations at the northern range limit having higher population growth rates than those at the southern limits. While the pelagic prey that we examined have relatively fast generation times, changes in population productivity as a mechanism for poleward shifts in distribution may explain their slower pace of range extensions in comparison to highly mobile marine predators where the mechanism of distributional shifts is directed movement.61. Endothermic predators, while capable of tolerating a wide range of temperatures, may have a competitive predatory advantage by shifting faster.Physiological and ecological processes underlying latitudinal trends in species richness for endotherms and ectotherms may also play a role in the rapid distributional shift we observed in long-finned pilot whales. For ectothermic prey species, important biological processes such as swimming speed and metrics of visual abilities are slower in cooler waters. As a result, prey in cool waters are easier for endothermic mammals and birds to capture while predatory sharks are easier to avoid, and marine endotherms thus have a competitive advantage over ectothermic predators in cooler waters63, but given the high energetic costs of endothermy outside of the thermoneutral zone64, these species might be expected to show rapid climate responses at the edge of their ranges should water temperatures fall outside of the thermoneutral zone. The upper and lower critical limits of the thermoneutral zone are unclear for most cetacean species since traditional study methods such as respirometry are typically not feasible (though see65). It is therefore not currently possible to assess habitat shifts in cetaceans relative to thermal tolerance. However, endothermy in the highly conductive marine environment is associated with a number of other traits, such as large body size and thus high motility, that are expected to influence climate responses20. Thus, whether due to direct effects of endothermy or associated traits, cetaceans may be expected to show climate responses that differ from their prey species. Of course, species-specific traits and factors such as fixed breeding areas, observed in baleen whales, may also influence climate responses of cetaceans.The role of thermoregulation in mediating climate responses of endothermic predators relative to their prey merits further investigation. Endotherms such as cetaceans are capable of tolerating a wide range of temperatures through both behavioral and physiological mechanisms36. Our results also suggest that the relative shift of cetaceans and their prey may depend on the extent to which surface temperatures influence the thermal budget of cetacean species, and the ability of fish and invertebrate prey species to move deeper in the water column rather than poleward to stay within their preferred temperature range. Further, the climate velocity observed in the NEUS exceeds that expected for other regions, including nearby regions such as the South Atlantic Bight, given the rapid pace of climate change observed in the northern reaches of the NEUS. Our estimates of climate velocity were calculated at a finer spatial scale than previous studies  and thus resulted in greater spatial variability and a higher range of climate velocities than observed in previous studies. Analyzing SST at a higher resolution is particularly important in the NEUS and broader Northwest Atlantic in order to accurately resolve the position of the Gulf Stream and temperatures on the continental shelf66. This approach allowed us to examine differences in SST gradients and climate velocities between subregions and species habitats within the NEUS.The extent to which our findings apply to other cetacean species and ecosystems is unclear given the lack of reliable time series to examine the effects of environmental change on cetaceans50, which suggest that longfin squid, shortfin squid, Atlantic mackerel and Atlantic herring dominate the diet of long-finned pilot whales. Long- and short-finned squids which were found to be prevalent in long-finned pilot whale diet in the NEUS in the early 1990s may represent a smaller contribution to pilot whale diet in this region today due to the marked shifts observed in pilot whale but not squid distribution. Contemporary studies of long-finned pilot whale diet in the NEUS would allow these predictions to be assessed.Our analyses of changes to the spatial distribution of pilot whales and their prey suggests that in recent years, long-finned pilot whale diet may have changed. Few studies have quantified the diet of long-finned pilot whales and thus our current understanding of long-finned pilot whale diet may be incomplete and may not reflect temporal changes in diet. We focus here on the best available data, taken from studies conducted in the early 1990s27, and bioenergetics studies indicate that marine mammal predation on fish stocks in the NEUS is significant and may equal removal by commercial fisheries70. While large whales have higher daily consumption rates, the annual population-level consumption of smaller odontocetes can rival or exceed that of large whales due to their higher abundance and longer residence in the NEUS. For example, pilot whales are estimated to consume more than 60 thousand metric tons of squid each year, more than three times as much squid as any other marine mammal species and considerably more squid than is removed by commercial fisheries in the NEUS each year70. Our results suggest that long-finned pilot whales have shifted poleward and today occur less frequently in the southern reaches of the NEUS than they did previously. Declines in top predators and mismatches in the occurrence of predators and prey have the potential to disrupt trophic interactions and can restructure marine communities76. Thus, our findings highlight the importance of assessing how climate change is changing the distribution of cetaceans relative to their prey in order to understand the ecological implications of future climate-driven change.The implications of mismatches between cetaceans and their prey are considerable. Interactions between predators and prey play a major role in maintaining the structure and stability of ecosystemsWe show here that shifts in the distribution of a cetacean species was correlated with thermal niches (SST) rather than shifts in the distribution of its prey. Our results suggest that species traits such as thermoregulatory strategy, motility, body size, depth tolerance, and diet specificity may dictate whether or not species track climate velocity. We found that range shifts of marine endotherms can outpace shifts in their ectothermic prey species because the mechanisms underlying the shifts differ for predator and prey. Climate-driven shifts of predators that are decoupled from those of their prey may have broad implications for food web ecology and ecosystem structure.46, but detailed oceanographic assessments of climate velocity within the NEUS that are independent of species distribution data and account for both spatial and temporal gradients in temperature are lacking.The Northeast United States (NEUS) is a highly productive marine ecosystem bounded by Cape Hatteras, NC to the south, the Scotian Shelf to the north and the Gulf Stream to the east that supports important commercial and recreational fisheries. The NEUS lies at the nexus of warm, salty slope water associated with the Gulf Stream moving north and cold, less-saline Labrador slope water flowing south. Water properties at depth in the NEUS are heavily influenced by the volume of equatorward-flowing Labrador Slope water such that when the volume of Labrador Slope water is high, water is cold and fresh on the shelf. When the volume of Labrador Slope water is low, the Gulf Stream is in a more northerly position and water on the shelf is warm and salty. As these two water masses converge in the NEUS, they create a strong gradient in temperature. In summer, the temperature gradient can differ by almost 20 °C from Cape Hatteras to Nova Scotia, but high interannual variability in water temperature causes the location of isotherms to vary greatly. Water temperatures have shown some of the highest rates of warming in the world in recent decades54. The two pilot whale species, short- and long-finned pilot whales , are very difficult to distinguish at sea and as a result species-specific observations in the NEUS, where the two species overlap, are limited and the range of long-finned pilot whales is not well understood 49. Observations from stranding events and fisheries bycatch can thus provide important information on the distribution of pilot whales at the species level. Long-finned pilot whales frequently strand in groups of up to several hundred individuals, although the causes of these mass stranding events are not well understood77. Strandings enable close examinations of morphology, allowing species-specific trends to be examined for these species which are otherwise difficult to identify. Data on long-finned pilot whale diet in the NEUS are limited, but stomach content analyses found that long-finned squid, short-finned squid, Atlantic mackerel, and Atlantic herring dominated the diet50. These four species were therefore used to represent pilot whale prey in our analyses.Long-finned pilot whales are deep-diving odontocetes that feed on fish and squid and are capable of diving to more than 800 m to forage51. Shifts in the center of biomass have been observed in both of these species that are tightly coupled with sea surface temperature concomitant with increases in population size and area occupied78.Atlantic herring and Atlantic mackerel are two of the most common pelagic fish species in the NEUS with the distribution of Atlantic herring being more northerly than Atlantic mackerel. Both species move south in the winter and undergo an extensive poleward migration in the spring. Atlantic herring are known to undergo large migrations on the order of 1500 km each year79. They are annual species and spawn year-round. Like many species in this temperate marine system, long- and short-finned squid migrate offshore and south in the autumn to overwinter and then migrate inshore and north as waters warm in the spring, but their annual migration is much less extensive than Atlantic herring or Atlantic mackerel. These species are known to undertake diel vertical migration and as such must respond to environmental factors throughout the water column80. Shifts in distribution over multidecadal time scales have not been detected in these species81.Long-finned squid and short-finned squid are prey for many fish predators in the Northwest Atlantic and both support commercial fisheries. They are widely distributed with the range of long-finned squid extending from Newfoundland to Venezuela and the range of short-finned squid extending from Iceland to the east coast of Floridahttps://www.fisheries.noaa.gov/national/marine-life-distress/national-stranding-database-public-access). Since the number of pilot whales stranding was not expected to be representative of pilot whales occurring offshore at that time and location, individual pilot whales that stranded on the same day within a distance of 30 km were considered part of the same stranding event when analyzing the latitude of stranding events in each year so as not to bias analyses by giving more weight to larger stranding events. In these cases, the mean latitude of stranding locations of multiple individual was used to represent the latitude of the stranding event. Cape Hatteras has historically been considered to be the southern extent of the range of long-finned pilot whale range49, and the strandings data agreed with this assessment. While several strandings of long-finned pilot whales occurred at or just north of Cape Hatteras, only three stranding events were recorded south of Cape Hatteras during the study period . These strandings were clear outliers in the dataset, occurring more than 550 km south of other strandings, and were excluded from analyses.We use data from strandings and fisheries bycatch to assess changes in the distribution of long-finned pilot whales in the NEUS in relation to changes in sea surface temperature (SST) between 1992 and 2016. Strandings data were obtained from the U.S. National Stranding Database collected by the Greater Atlantic Region Marine Mammal Stranding Network (GARMMSN) and the Southeast Marine Mammal Stranding Network (SEMMSN) from 1992 to 2016, which together cover strandings throughout the eastern seaboard of the U.S. Following amendments to the U.S. Marine Mammal Protection Act (MMPA) in 1992, the Marine Mammal Health and Stranding Response Program was formalized resulting in standardized data collection by stranding networks across the country which we used to assess changes in the latitude of strandings through time. Level A data collected by stranding networks in the U.S. must be reported to the National Stranding Database, and includes information such as species identification, date and location of strandings, and the condition of the stranded animal  and the At Sea Monitoring (ASM) Program (https://www.fisheries.noaa.gov/new-england-mid-atlantic/fisheries-observers/sea-monitoring-northeast) run by the National Marine Fisheries Service (NMFS) Northeast Fisheries Science Center (NEFSC). These programs place independent observers aboard bottom trawls to record bycatch and detailed data on each trawl . We used NEFOP data from 1992 on and ASM data from 2010, when the ASM program was initiated, to examine locations and rates of pilot whale bycatch. We refer to these data collectively as observer data. Most occurrences of pilot whale bycatch in observer data (93%) were not identified to species. As noted in stock assessment reports for long-finned pilot whales 49, all pilot whale bycatch in bottom trawls occurs in regions is attributed to long-finned pilot whales due to the location of these trawls relative to the typical habitat of long- and short-finned pilot whales. Our analysis of NEFOP and ASM data agreed with this assessment; any pilot whale bycatch identified to the species level consisted exclusively of long-finned pilot whales, and morphological measurements and habitat assessments indicated that observed pilot whales were long-finned pilot whales. For example, all adult female pilot whales that were taken as bycatch were greater than 400 cm in length, and a recent study of pilot whale morphometrics from the eastern seaboard of the United States indicated that mature female short-finned pilot whales are considerably less than 400 cm in length , and all observations of pilot whale bycatch occurred in temperatures below 22 °C.Long-finned pilot whales are taken as incidental catch within the Northeast bottom trawl fishery, which constitutes the majority of annual human-caused mortality of long-finned pilot whales in the NEUS https://www.nafo.int/Portals/0/PDFs/sc/2014/scr14-024.pdf ). Details of the data collection for this survey are outlined in 82. Since the 1980s, there has been no significant change in the timing of the fall survey, with surveys conducted between September and December of each year81, and the mean annual latitude and longitude of the stations has not changed over time. We used only strata that were consistently sampled  and data have been corrected for changes in gear and vessels as outlined in 81. The NEFSC also conducts a spring trawl survey using the same methodology, but our analyses focused on the fall survey as observations of fisheries bycatch suggested that long-finned pilot whales were most frequently observed in the NEUS between September and February  fall trawl survey, which uses a stratified random design and has occurred in the spring since 1968 and fall since 1963 (https://podaac.jpl.nasa.gov/dataset/CMC0.2deg-CMC-L4-GLOB-v2.0. ). To match the timing of biological datasets, we used fall (September to November) climatologies of SST to examine changes in SST from 1992 to 2016 within the NEUS and subregions therein  in the NEUS using data from the Canadian Meteorological Center , while all other analyses were conducted in R (version 4.0.3). We used linear regressions to examine changes in the following parameters over time: mean SST in sub-regions of the NEUS , resulting in an index of the velocity of temperature change (km/year). As with other SST analyses, we used mean fall SST from the CMC at a 0.2 degree resolution to assess temperature gradients, using the slope of a linear model fit through each year of the study period to compute temperature gradients17 .To assess whether species were shifting faster or slower than expected based on changes in water temperature, we compared observed species shifts to estimates of local climate velocityWe examined observed distributional shifts relative to climate velocity within the core ranges of each species and examined spatial patterns in the pace of climate change within the NEUS by comparing climate velocities within NOAA Ecological Production Units (Gulf of Maine, Georges Bank, Southern New England, Mid-Atlantic Bight as well as the adjacent Scotian Shelf; Fig. Supplementary Information.


Over the past decade, various cell and gene therapy approaches have led to advanced therapy medicinal products that offer tremendous hope for patients suffering from rare genetic diseases. This especially applies to conditions affecting the musculoskeletal system or the skin, which represent the largest organs in the human body. The impairment of muscles, bone or skin due to a genetic abnormality usually has a large impact on the whole organism, and some severe hereditary conditions, such as Duchenne muscular dystrophy, are not particularly rare.In this research topic on novel therapies, we aimed to highlight promising recent developments, challenges, and interdisciplinary scientific questions. We encouraged our colleagues to submit relevant articles of all types and included very different contributions, ranging from original research findings in a mouse model of human disease and with patient-derived induced pluripotent stem cells (iPSC) to a phase II/III clinical trial protocol.Koch and Koster outlines the rationale of studying rare diseases and the recent approaches they and others are applying to tackle the complexity of two developmental disorders that belong to the group of ectodermal dysplasias. They discuss the challenges for researchers in this field and focus on correcting phenotypes in the most severely affected tissues, such as wounded skin, by cell therapy strategies using genetically corrected iPSC.The introductory perspective article by Boyer et al. review myogenic cell transplantation for various genetic and acquired muscle disorders including Duchenne muscular dystrophy, oculo-pharyngeal muscular dystrophy, mitochondrial myopathies, inclusion body myositis, and sphincter incontinence. This paper provides deep insights into common or disease-specific problems that have so far limited the clinical success of myogenic cell therapy. It highlights the need for scientific, pharmaceutical and regulatory communities “to join forces and work together to produce mutual guidelines for preclinical core requirements” as well as for openness to innovative study designs in order to facilitate the translation of promising experimental results into clinical trials. This is also true for an unprecedented strategy to treat the most frequent ectodermal dysplasia (Kossel et al. illustrates this point with data showing that disturbed vertebral bone development in EDA1-deficient mice can be corrected by timely EDA1 replacement. It emphasizes tissue-specific requirements for the timing of interventions and an opportune way to overcome drug-targeting hurdles.ysplasia  which isKoller and Bauer discuss emerging treatment concepts based on gene replacement or genome editing, while De Rosa et al. present the protocol of a planned clinical trial of combined cell and gene therapy, which was prompted by the successful treatment of two adults and one severely affected child with junctional epidermolysis bullosa (The two final chapters of this research topic address new gene and cell therapy approaches to treat epidermolysis bullosa, a severe genodermatosis characterized by blistering of the skin upon minor mechanical trauma.  bullosa .


This narrative review elaborates on neural structures and particularities of arachnophobia. Current treatment options are discussed and future research questions are highlighted.Recent fMRI studies on specific animal phobias, particularly spider phobia (arachnophobia), have identified a large variety of specific brain regions involved in normal and disturbed fear processing. Both functional and structural brain abnormalities have been identified among phobic patients. Current research suggests that both conscious and subconscious fear processing play a crucial role in phobic disorders. Cognitive behavioral therapy has been identified as an effective treatment for specific phobias and has been associated with neuroplastic effects which can be evaluated using current neuroimaging techniques. Recent research suggests that new approaches using virtual (VR) or augmented reality (AR) tend to be similarly effective as traditional “ Animal phobia is a type of specific phobia, which is classified under the Anxiety Disorders section of the DSM-5 . To meetEarly neuroimaging studies of fear conditioning, as well as more recent experiments, have found evidence of an activation of the amygdala, the anterior cingulate cortex, and the insula—when healthy participants are confronted with conditioned fear-evoking stimuli independent of the task design . These sResting state fMRI paradigms suggest that the anterior cingulate cortex (ACC), as well as limbic- and hypothalamus- related areas, is functionally connected to areas responsible for affective processing . AlthougIn general, current fMRI research studies indicate that a large array of brain regions are involved in both normal and phobic fear processing; however, the activation in phobic states has been found to be stronger . The strInterestingly, individuals suffering from spider phobia compared to non-phobic individuals show an increased fear response pattern in the mid-insula, dorsal anterior cingulate, and the ventrolateral PFC that grows linearly with perceived danger. Thus, these brain regions seem to hold a quantitative representation of the exaggerated fear response . While mAs mentioned above, a predominantly known key structure in fear processing is the amygdala, which usually shows hyperactivity in individuals with phobia . IncreasWhile structures of the network mentioned above are involved in fear processing in general, their specific roles seem to be more complex. The temporo-spatial activation of different brain areas in spider phobia can especially be linked to different emotion regulation deficiencies. While automatic emotion regulation deficiencies seem to be reflected by increased activity in the insula and reduced activity in the ventromedial PFC, effortful emotion regulation deficits are reflected in an enhanced activity in medial PFC areas . DiffereBoth functional and structural abnormalities like thinning of the right ACC can be found in patients with spider phobia . The sizPhobias can not only be associated to neural abnormalities but also associated with physiological changes. When exposed to a phobic stimulus, patients with phobia show somatic response patterns or “markers” which differ from healthy controls, such as greater heart rate amplitudes and hypervigilance, as well as increased pupillary dilatation, electrodermal response, and self-reported affect , 41. AltThe evidence for sex differences in activation patterns as a response to phobic stimuli is still not entirely clear. There is some evidence that phobic activation patterns may differ between males and females. These differences might be due to different attention styles and self-control strategies  as well Past research has relied on Seligman's theory of prepared learning , 46 to eStudies on the biological origin of fear and phobic reactions have highlighted the role of structural differences in anxiety sensitivity, such as the inclination to interpret physical symptoms as potentially threatening. Anxiety sensitivity is found to be correlated to right anterior insular cortex size (volume and thickness) in patients with spider phobia . Other sNot surprisingly, a crucial part in the neurobiological understanding of phobic disorders is the involvement of the amygdala. While common fear theories postulate that its activation is independent from attentional processes , others Phobic stimuli are assumed to have greater affective salience in patients with phobia and therefore gain a more rapid access to awareness. Schmack et al.  demonstrcovariation bias is a common bias that occurs among individuals with phobias. There is evidence suggesting that individuals with phobias tend to overestimate the association between the feared stimulus and aversive consequences . In addition, spider-phobic individuals can be reluctant to confront their fears in reality. Hence, treatment options using virtual or augmented realities might be an interesting alternative from different viewpoints. Augmented Reality (AR) is a new approach to treatment that allows enriching real-life environments with virtual elements and has been successfully applied in various settings including treatment of mental health disorders , in contrast, describes completely simulated, artificial environments—an approach which has recently gained popularity to treat psychiatric diseases, in particular anxiety disorders . The sucrvations . Severalrvations , 86. Fur after 3 , 88 and  after 3 . Some st after 3 ].While technically new approaches promise many advantages in the field of treating natural object phobias (such as spider phobia), one can question if unpredictable nature elements like a real threat can be completely replaced by artificial elements at this stage. More research has to be conducted to assess the similarity between simulated human behavior and real-life behavior. Concerns regarding addictive behavior in virtual reality have also been raised . Becausein-vivo exposure therapy, and superior to no treatment, and comes along with several advantages such as accessibility [e.g.  and emerging approaches including virtual or augmented reality.Functional MRI has proven to be a strong research tool to investigate the neural basis for both normal and phobic fear. Accordingly, research over the past decade has been able to identify a large array of brain regions associated with fear processing: not only those involved in emotional and attentional processing, but also for the detection of body states and motor behavior. While the amygdala seems to be mainly involved in automatic fear processing, albeit not fully independent of attentional processes, other structures as the insula, ACC, and dorsomedial PFC appear to be directly related to fear processing requiring attentional resources . As a coin-vivo exposure therapy while increasing the accessibility and acceptance of treatment opportunities and supporting therapy-resistant patients (Cognitive behavioral therapy has been proven as a very effective clinical treatment and its effects can be observed even at a neural level . The newpatients , 83. VirJH and AR substantially contributed to the conception of the work and drafting the first version of the document. UM, NM, KD, MR, and MN-H contributed to the analysis and critically revising the document as well as providing final approval of the version to be published.KD is a member of Janssen Pharmaceuticals Steering Committee Neurosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Alterations in the accumulation and composition of the extracellular matrix are part of the normal tissue repair process. During fibrosis, this process becomes dysregulated and excessive extracellular matrix alters the biomechanical properties and function of tissues involved. Historically fibrosis was thought to be progressive and irreversible; however, studies suggest that fibrosis is a dynamic process whose progression can be stopped and even reversed. This realization has led to an enhanced pursuit of therapeutic agents targeting fibrosis and extracellular matrix-producing cells. In many organs, fibroblasts are the primary cells that produce the extracellular matrix. In response to diverse mechanical and biochemical stimuli, these cells are activated or transdifferentiate into specialized cells termed myofibroblasts that have an enhanced capacity to produce extracellular matrix. It is clear that interactions between diverse cells of the heart are able to modulate fibroblast activation and fibrosis. Exosomes are a form of extracellular vesicle that play an important role in intercellular communication via the cargo that they deliver to target cells. While relatively recently discovered, exosomes have been demonstrated to play important positive and negative roles in the regulation of fibroblast activation and tissue fibrosis. These roles as well as efforts to engineer exosomes as therapeutic tools will be discussed. Fibrosis, or accumulation of excessive extracellular matrix and matricellular proteins, occurs in response to tissue damage or stress in most organs and is evident in many cardiovascular diseases ,2. CardiNumerically, fibroblasts form the largest cell population in the heart and are classically defined as the primary cell type involved in the synthesis and degradation of the extracellular matrix, which provides structure for cardiomyocytes and other cardiac cells . It is nIntercellular communication is critical for development and homeostasis in multicellular organisms. This is particularly true in the heart which includes a number of resident cell types  and diverse transient cells . Communication between these cells can be accomplished via physical cell-to-cell interactions or via secreted factors, including factors  delivered via extracellular vesicles such as exosomes. Direct physical interactions between cells involve diverse structures including tight junctions, adherens junctions, desmosomes, and gap junctions. Of these, gap junctions are well-established mediators of direct cell-to-cell communication. In vertebrates, these are composed of proteins termed connexins, which form channels allowing regulated transfer of small molecules such as ions, peptides, and miRNAs between cells. Experimental deletion of connexin proteins in animal models results in developmental defects in multiple organs including skeletal muscle, blood vessels, bone, heart, and others ,14. HearMany factors, including growth factors, hormones, and cytokines, are secreted directly into the extracellular space and mediate communication between cells typically via specific receptors and the activation of signaling pathways and gene expression programs. A number of secreted factors have been shown to stimulate myofibroblast formation and fibrosis including paracrine factors from cardiomyocytes and inflammatory cells and autocrine factors from myofibroblasts themselves. These secreted factors include cytokines such as interleukin-13 (IL-13) and transforming growth factor-beta (TGF-β), growth factors such as platelet-derived growth factor (PDGF), and hormones such as angiotensin II. Most of these factors are synthesized and released from cells via secretory pathways; however, it has become apparent that some of these factors and other “cargo” are transported via extracellular vesicles to regulate myofibroblast formation and fibrosis.Extracellular vesicles are membrane-bound vesicles released into the extracellular space by most, if not all, cells. These vesicles carry lipids, proteins, nucleic acids, and metabolites that are derived from their cell-of-origin. Pioneering studies over seven decades ago illustrated the functional existence of platelet-derived extracellular materials in the blood clotting process that is removed following ultracentrifugation of blood . MicroscThe classification of extracellular vesicles is continually evolving but most schemes distinguish three major subtypes including exosomes, microvesicles, and apoptotic bodies . Though A number of functions have been postulated for extracellular vesicles; however, interest in these vesicles grew exponentially with the realization that they are able to mediate intercellular communication via delivery of their cargo to recipient cells. They can mediate communication locally within the same tissue or, since they are released into the bloodstream and other bodily fluids, between distant organs . The comExosomes are a subset of extracellular vesicles that were originally thought to represent a mechanism for disposal of “cellular debris”. Mechanisms regarding their formation, secretion and uptake are beginning to be elucidated and will be briefly addressed here. These topics have been extensively discussed in recent reviews ,30.Biogenesis—Exosomes are produced via the endosomal system beginning with invagination of the plasma membrane to form early endosomes. Early endosomes fuse to form late endosomes with invagination of the endosomal membrane producing intraluminal vesicles. Late endosomes or multivesicular bodies can either fuse with lysosomes or autophagosomes to be degraded or fuse with the plasma membrane to release exosomes and their contents into the extracellular space.While the molecular mechanisms regulating the formation and secretion of exosomes are far from understood, studies have indicated two general pathways, one dependent upon the endosomal sorting complex for transport proteins (ESCRT) and another that is ESCRT-independent . Four diESCRT-independent mechanisms of intraluminal vesicle formation have more recently been described through perturbation studies, which, despite eliminating ESCRT proteins, retained multivesicular body formation . One sucAnother potential ESCRT-independent pathway may be initiated by tetraspanins. The tetraspanins are a large family of integral cell surface proteins characterized by four transmembrane domains. These proteins are highly conserved and participate in a number of cellular processes including cell adhesion, differentiation, and tumor invasion ,38. SeveTrafficking of exosomes and secretion—As mentioned previously, multivesicular bodies can either be targeted to lysosomes for degradation or to the plasma membrane for release of exosomes. The mechanisms underlying the sorting of multivesicular bodies is beginning to be elucidated. In B-lymphocytes, two pools of multivesicular bodies have been identified based on cholesterol content . MultiveSimilar to other cytoplasmic vesicles, interactions of multivesicular bodies with the cytoskeleton, small GTPases and molecular motor proteins are essential for their transport to the cell surface. Increased or decreased expression of cortactin, an actin cytoskeletal regulatory protein, has resulted in enhanced or reduced extracellular vesicle secretion, respectively . CytoskeCells only release a very small proportion of their cellular contents via exosomes and the degree and rate of exosome secretion is dependent on the cell type and pathophysiological status of the cell. Tumor cells have been shown to release substantially more exosomes than non-tumorous cells . VariousAs mentioned above, fibroblast activation and fibrosis can be stimulated by mechanical forces. The effects of mechanical forces on exosome secretion are only recently beginning to receive attention. Studies in the cardiovascular system, where cells are continually exposed to changes in the mechanical environment, illustrated that experimentally induced increases in cardiovascular load via transaortic constriction elevated serum concentration of exosomes approximately 3-fold compared with control animals . TreatmeComposition—Exosomes contain diverse proteins, lipids, and nucleic acids. The composition of exosomes is quite variable and is dependent in part on the cell type and pathophysiological status of the cell. Studies have even illustrated differences in content between exosomes released at the basolateral versus apical aspects of epithelial cells . Recent Particular miRNAs are enriched in exosomes relative to the whole cell, indicating that exosome content is regulated and that miRNAs can be targeted to the exosomes. Some mRNAs are also preferentially enriched in exosomes . MultiplExosome uptake by target cells—Once released into the extracellular environment, the ability of exosomes to impact physiological or pathological processes is typically dependent on uptake of the exosome and its cargo by target cells. The uptake of exosomes by recipient cells is far from understood but is thought to be mediated by multiple processes including phagocytosis, macropinocytosis, plasma membrane fusion and endocytosis via clathrin-dependent and independent mechanisms recently reviewed in . InteresUnderstanding of the regulation of pathophysiological processes by exosomes in the heart is continuing to emerge, but it is clear that exosomes can have beneficial and detrimental effects on cardiac health . AlteratPreclinical and clinical studies have illustrated the effectiveness of stem cell therapy in improving outcomes following myocardial infarction . NumerouCirculating exosomes are being used as biomarkers of pathological conditions including cardiovascular disease (discussed below) and also impact cardiovascular function. Exosomes isolated from non-pathological animals delivered into the circulation of rats prior to induction of myocardial infarction diminished infarct size . These eFibroblast activation and fibrosis can be induced by diverse mechanical and chemical stimuli. Recent studies have emerged indicating roles for exosomes in both negative and positive regulation of fibroblast activation and fibrosis, which is likely a reflection of the heterogeneity of exosomal cargo from diverse cells ,72. A vaExosomes and miRNAs that promote fibroblast activation and fibrosis—As mentioned previously, exosomes carry a variety of cargo that is potentially involved in paracrine signaling between cells including proteins, lipids, mRNAs, and miRNAs. miRNAs  are highly conserved non-coding RNA molecules that are involved in the regulation of target gene expression. While they do not encode any protein, miRNAs regulate target gene expression post-transcriptionally and extensive research has focused on these as carriers of bioregulatory information in exosomes. A number of miRNAs have been shown to induce fibroblast activation and fibrosis in animal models or in vitro studies. The specific miRNAs involved appear to be numerous and their molecular mechanisms quite diverse ,97. Schistosoma infection compared with healthy individuals [Exosomal miRNAs in serum have been evaluated as potential biomarkers of diverse diseases including fibrosis and serum-derived exosomes can stimulate fibrosis. In one study, a panel of serum-derived exosomal miRNAs were able to distinguish patients with hepatic fibrosis resulting from chronic ividuals . One of ividuals . ExosomeExosome-mediated communication between resident fibroblasts and other resident myocardial cells can also be pro-fibrogenic. Several cardiomyocyte-derived exosomal miRs have been shown to promote fibroblast activation and fibrosis. miR-208a expression was elevated in cardiomyocytes in animal models of heart disease including myocardial infarction and doxorubicin-induced cardiotoxicity . ExpressAlong these lines, previously unpublished studies from our group have been carried out to evaluate the role of exosome-mediated communication between heart myocytes and fibroblasts in the pro-fibrotic response to alcohol abuse. Chronic abuse of alcohol deleteriously impacts most organ systems and approximately one-third of individuals who abuse alcohol long-term develop alcoholic cardiomyopathy. This condition is accompanied by myocardial remodeling that includes cardiomyocyte apoptosis and fibrosis and often results in heart failure . In thesmiRNAs derived from cardiomyocyte exosomes not only act on fibroblasts directly but can modulate their activity indirectly by acting on other cells that impact fibroblast activity and fibrosis. For instance, several studies have shown that cardiomyocyte-derived exosomes can modulate inflammatory cell behavior and phenotype ,103. miRIn addition to secreted biochemical factors, exosome-mediated communication between inflammatory/immune cells and fibroblasts may be involved in cardiac fibrosis. Expansion and activation of CD4+ T cells facilitates myocardial remodeling; however, the molecular mechanisms of this are not entirely known . TreatmeExosomes and miRNAs that inhibit fibroblast activation and fibrosis—A number of exosomal-derived miRNAs have been identified that inhibit fibroblast activation and fibrosis and are being proposed as potential therapeutic candidates. In particular, exosomes derived from diverse stem cells appear to be protective against myocardial damage and fibrosis. For instance, treatment of rats with exosomes derived from mesenchymal stem cells was shown to prevent cardiac inflammation and fibrosis and improve cardiac function following myocardial infarction even better than treatment with stem cells themselves . In vitrExosomes from non-stem cells including inflammatory cells have also been shown to protect against myocardial damage. During cardiac injury, activated macrophages secrete exosomes that are enriched in miR-155 . FibroblmiR-29 has been studied extensively as inhibitory to fibrosis of the heart and other organs and has a unique role in modulating extracellular matrix expression directly. The miR-29 family contains three members, miR-29a, miR-29b and miR-29c, encoded by two gene clusters. miR-29 family members directly target at least sixteen extracellular matrix components including several collagen isoforms, elastin and fibrillin . miR-29 Non-miRNA Cargo and Fibrosis—Exosomes also have the ability to modulate the extracellular matrix via other mediators in addition to miRNAs. While these have not been as extensively studied as miRNAs, there are examples of their roles in fibrosis of the heart and other organs. Other types of RNAs can be transported by exosomes and impact fibrosis either directly or indirectly through modulation of the inflammatory response. Following kidney injury, exosome production is increased by renal tubule epithelial cells . ExosomeProteins associated with exosomes not only modulate fibroblast behavior but may also remodel the extracellular matrix directly. Alterations in the protease to anti-protease balance, particularly neutrophil alpha1 antitrypsin, results in extracellular matrix degradation in the lungs and chronic obstructive pulmonary disease (COPD). Recent studies have illustrated that exosomes from activated polymorphonuclear leukocytes (PMNs) may contribute to COPD and other respiratory diseases associated with extracellular matrix degradation . IncreasAs mentioned above, the cargo carried by exosomes that modulate fibrosis and fibroblast activation, their cells of origin and their mechanisms of action are quite diverse. The specific exosomal cargo that have been functionally demonstrated to affect cardiac fibrosis are summarized in Due to difficulties in delivering fragile therapeutics to the pathological myocardium, aggressive attempts are being made to identify novel delivery methods including nanomaterials, hydrogels, and others. Exosomes possess a number of advantageous properties that have led to their exploration as potential carriers of therapeutic cargo . These iAn important consideration for optimizing exosomes as a delivery vehicle is modulating their content to treat particular pathological conditions. A hurdle in this regard is loading cargo across the exosomal membrane. Several approaches have been developed to enhance the loading of specific molecules into exosomes via cargo pre-loading or post-loading strategies. The first approach is to engineer the donor cells producing the exosomes to express the component(s) of interest, which is then incorporated into exosomes as they form. Various vectors that express proteins or miRNAs of interest have been utilized to engineer exosome-producing cells and exosomes then harvested for downstream applications. This approach has been taken in a number of studies to load exosomes with specific miRNAs identified to treat particular pathological conditions. For instance, after miRNA-124a was identified as a potential treatment for glioblastoma, mesenchymal stem cells were engineered to highly express this miRNA via lentiviral infection . ExosomeThe cargo post-loading approach has been used to load specific cargo, such as therapeutic drugs or compounds, directly into purified exosomes. Loading may be accomplished via passive mechanisms in the case of hydrophobic compounds that diffuse through the lipid bilayer of the exosome or active mechanisms including electroporation or sonication of the exosomes. Passive loading efficiency varies greatly depending on the properties of the cargo and incubation parameters . An advantage of exosomes for drug delivery is their ability to transport multiple classes of cargo simultaneously. Recent studies have engineered exosomes as a potential approach to more effectively treat cancer cells resistant to the chemotherapeutic compound 5-fluorouracil (5-FU). Purified exosomes were loaded with an inhibitor to miRNA-21 and 5-FU by electroporation  and demoDelivery of exosomes into the circulation often leads to accumulation primarily in the liver and spleen with much less accumulation in the heart or other organs. Approaches are being developed to improve cell-specific targeting of exosomes largely through incorporation of molecules into the exosomal membrane. Advances in this area would allow systemic delivery while reducing off-target effects and potentially lowering the effective dose of exosomes required for treatment. Similar to engineering the cargo delivered by exosomes, modulating the exosome surface could be done via engineering the donor cells or the exosomes themselves. The approaches for therapeutic exosome targeting include incorporation of surface targeting peptides, antibodies, receptor proteins or signaling molecules . Several3O4 core and a silica shell. The outer layer of these nanoparticles contained antibodies that recognized CD63 of exosomes or myosin light chain surface markers of injured cardiomyocytes. In response to a magnetic field, nanoparticles were recruited to the injured myocardium and exosomes released. This resulted in reduced infarct size and improved left ventricular function.An innovative approach has been used to attract exosomes from the circulation to damaged myocardium following myocardial infarction using magnetic nanoparticles . The invThe current gold standard for assessment of many diseases including fibrosis involves invasive procedures such as tissue biopsies that often include significant patient risks. Development of biomarker profiles of disease that can be obtained from biological fluids including serum are being aggressively pursued. The properties of exosomes including relatively stable cargo that are reflective of pathophysiological status of tissues makes these ideal candidates for assessment of pathogenesis. The utilization of exosome-derived biomarkers diagnostically is most advanced in the cancer field where exosomal miRNA signatures have been developed for rectal, cervical, and other cancers ,141 and With regards to cardiovascular disease, exosomal miRNA patterns are being established for several conditions  and may As mentioned previously, a number of miRNAs have been identified that are associated with fibrosis. Analysis of exosomes from patients with idiopathic pulmonary fibrosis has demonstrated an increase in miRNAs indicative of fibrosis  and a decrease in anti-fibrotic miR-141 . In a seTechnology is also being advanced to more effectively isolate and detect exosomal biomarkers. Exosomes are recovered from biological fluids as a mixture with other components and require purification via methods that preferably provide high throughput, low contamination, and high recovery rate. Approaches that have been commonly utilized to purify exosomes include ultracentrifugation, ultrafiltration, size-exclusion chromatography, and immunological separation. Each has limitations including costly equipment, lack of sensitivity, low specificity and others. In recent years, microfluidics-based techniques have emerged as innovative approaches for exosome purification and detection . Due to The detection of miRNAs from biological fluids for diagnostic purposes is typically via polymerase chain reaction (PCR) or next-generation sequencing. Limitations in the clinical applicability of these including sensitivity of standard PCR and cost of specialized equipment are driving the search for alternative methods. A recent study presented a novel electrochemical biosensor-based approach to detect exosomal miR-181 in serum samples from healthy individuals and patients with coronary heart disease . This apFibrosis is a common consequence of tissue damage and is associated with a number of cardiovascular diseases including myocardial infarction, hypertension, aortic stenosis, atherosclerosis and others. Functional roles for exosomes and their cargo are being identified in fibroblast activation and fibrosis in the heart and other organs. These include both beneficial and detrimental effects likely due to specific cargo transported by exosomes under particular pathophysiological conditions. The reflection of exosomal cargo on the pathophysiological status of cells and tissues are making these valuable diagnostic biomarkers, and profiles are being established for multiple pathological processes. The size and structure of exosomes provide substantial benefits in the delivery and protection of cargo. These properties are being leveraged to engineer exosomes as systems for the delivery of therapeutic reagents.


COVID-19 has severely impacted mental health in vulnerable demographics, in particular older adults, who face unprecedented isolation. Consequences, while globally severe, are acutely pronounced in low- and middle-income countries (LMICs) confronting pronounced gaps in resources and clinician accessibility. Social robots are well-recognized for their potential to support mental health, yet user compliance  demands seamless affective human-robot interactions; natural ‘human-like’ conversations are required in simple, inexpensive, deployable platforms. We present the design, development, and pilot testing of a multimodal robotic framework fusing verbal  and nonverbal  social cues, aimed to improve engagement in human-robot interaction and ultimately facilitate mental health telemedicine during and beyond the COVID-19 pandemic. We report the design optimization of a hybrid face robot, which combines digital facial expressions based on mathematical affect space mapping with static 3D facial features. We further introduce a contextual virtual assistant with integrated cloud-based AI coupled to the robot’s facial representation of emotions, such that the robot adapts its emotional response to users’ speech in real-time. Experiments with healthy participants demonstrate emotion recognition exceeding 90% for happy, tired, sad, angry, surprised and stern/disgusted robotic emotions. When separated, stern and disgusted are occasionally transposed  but are easily distinguishable from other emotions. A qualitative user experience analysis indicates overall enthusiastic and engaging reception to human-robot multimodal interaction with the new framework. The robot has been modified to enable clinical telemedicine for cognitive engagement with older adults and people with dementia (PwD) in LMICs. The mechanically simple and low-cost social robot has been deployed in pilot tests to support older individuals and PwD at the Schizophrenia Research Foundation (SCARF) in Chennai, India. A procedure for deployment addressing challenges in cultural acceptance, end-user acclimatization and resource allocation is further introduced. Results indicate strong promise to stimulate human-robot psychosocial interaction through the hybrid-face robotic system. Future work is targeting deployment for telemedicine to mitigate the mental health impact of COVID-19 on older adults and PwD in both LMICs and higher income regions. Prevalence of dementia is further skyrocketing in LMICs; 63% of PwD already live in LMICs, where 70% of new cases occur es occur . In Indies occur . Lower-ies occur . Recent es occur .This global health crisis has become even more critical during the COVID-19 pandemic. However, planning and response to public health emergencies  often do not directly address mental health, in particular for vulnerable groups such as older adults and PwD . DementiThe need for mental health and psychosocial support of PwD and their carers worldwide is well-documented  both durSocially assistive robots (SAR) are well-documented for promise to support dementia and mental health , with stThere are several verbal and nonverbal interaction modes used by SAR to engage with humans—such as facial expressions, speech, gestures, or behavior—but the most effective communication mode in human-robot interaction (HRI) is largely considered to be speech . IntelliThe high cost of such complex interactive systems is oftentimes a barrier for deployment, especially in LMICs. While SAR have shown great potential to support PwD in clinical and residential environments, no research to date has developed and pilot tested mechanically simple and low-cost robotic solutions to support dementia care in challenging scenarios imposed by the COVID-19 outbreak in LMICs, particularly in India.(1) Propose a new multimodal robotic framework that integrates animated representation of emotions with a voice system supported by a cloud-based AI conversational engine for enhanced engagement in HRI.(2) Test human-robot multimodal interactions with healthy participants in the United Kingdom demonstrating the robot’s ability to adapt facial expressions to users’ speech in real-time and a strong user preference for multimodal vs. pure voice communication.(3) Introduce a user-centred procedure for cultural validation addressing telemedicine acceptance of robotic mental health support of older individuals and PwD. Modifications to our robotic platform based on this procedure as implemented in South India are presented, and the procedure is offered as a broader method for introduction of such technology in new cultural arenas and demographics.(4) Present a pilot study introducing the robot into practice for dementia support in LMICs through experiments conducted with people with dementia at the Schizophrenia Research Foundation (SCARF) in Chennai, India.The goal of this investigation is to design, develop, and test the feasibility of a social robotic platform to support people with dementia, during and following the COVID-19 pandemic. We are particularly interested in surmounting cost constraints and ease of use demands for utility in LMICs. In our previous work  we introResults demonstrate the capacity to deliver telemedicine cognitive engagement and mental health support through the hybrid face robot. Current work is targeting trials in South India with planned investigations on deployment in LMICs as well as wealthier nations.The ability to recognize, understand, and show emotions plays a fundamental role in the development of SAR capable of meaningful interactions . Facial Robotics researchers are faced with the question of whether to design physically embodied, fully actuated robots, or simpler and cheaper virtual agents. Literature has argued the level of a robot’s embodiment is key to develop trust and rapport, and may affect human judgements of the robot as a social partner . Ghazal have sugThe field of ML has recently experienced extraordinary progress in the development of IVA. These AI-powered systems interact with users using natural language and are able to generate relevant responses in the form of text, speech, or both. This technology started in the 1960s with ELIZA , which hIntelligent virtual assistants have been deployed in healthcare for delivering cognitive behavior therapy  or assisThe hybrid face robot integrates a digital face capable of showing facial expressions and a 3D printed faceplace to convey realism and depth, which can be flexibly added to the robot . The robThe robotic face is simply made of four facial features: eyebrows, eyelids, eyes, and lips, with a total of 13 degrees of freedom (DoF) illustrated in t, is defined as the weighted linear combination of a set of basis expressions The robot’s software design is based on a mathematical approach for emotion mapping, in which the robot’s expression state, ous work , this set and Mb, respectively) open and close simultaneously, while the mouth width, Mw, changes by 30% to simulate the elastic movement of a human mouth.Following this approach, the modeling of emotions can be manually and remotely controlled by selecting each expression’s intensity, which is in turn converted into a 13-value vector, defining the DoF of the desired facial expression . AdditioIntelligent Virtual Assistant); 2) optimizing the voice stream synchronization parameters in Max software; 3) modifying DoF for some expressions to improve recognition rates. Taken together, these improvements allowed us to:(1) Integrate the robot’s speech capacity with facial expressions for adaptable emotion in response to users’ speech in real-time.(2) Introduce the robot into practice for aging and dementia support in LMICs; a pilot study was conducted at SCARF India using the hybrid face robot as a telemedicine tool for remote cognitive engagement with a person with dementia through repeated sessions, in the form of Wizard of Oz experiment  at SCARDesigning Infrastructure) was applied in a set of three robot-assisted cognitive engagement sessions to a person with dementia using the telemedicine interface. Beyond demonstrating the feasibility of the clinician-robot-patient interface in telemedicine for mental health in LMIC setting, we wish to generate initial data on the hybrid face robot as an engagement tool with PwD in the cultural context of South India. A Wizard of Oz approach was used during the three sessions. Hence, a clinician located in a separate room controlled the robot’s range of facial expressions and spoke with the participant ‘through’ the robot  and show an open mouth (increase Mt and Mb). Though the tired expression showed 100% recognition, participants reported some confusion with stern and disgusted, which can be due to their similarity of partially-closed eyelids and low eyebrows. Despite the added human features, participants’ feedback indicated the addition of the faceplate was perceived unfavourably and the physical depth was poorly perceived. The majority (13 out of 15 participants) disliked the robot and its capacity to show facial expressions when the faceplate was added. We hypothesize our experiments lie on the downslope of the uncanny valley; at this negative gradient, an increase in human likeness  worsens the human response toward the robot as its partial human appearance moves toward the minimum in the valley. Adding the 3D faceplate to the robot’s digital face appears in this context to induce a stronger uncanny valley effect, which we have considered in subsequent human-robot experiments.Qualitative data from interviews indicates the need to adjust some features for the happy expression to increase its likeability, namely increase the eyebrows’ vertical height  and PwD in India. Stakeholders concurred that the possibility of using a hybrid face robot for remote cognitive engagement can potentially help in meaningful engagement of people with dementia at home and also alleviate the perils of social isolation. Plans to deploy the robot as a remote platform to deliver regular cognitive engagement with more participants are underway. Ultimately, these findings suggest the use of this mechanically simple robotic platform for remote cognitive engagement may enhance mental health care and mitigate the impact of COVID-19 on people with dementia.Emotion Recognition). Recognition may show differences due to age, cultural context, and cognitive state. Hence, expressions of the hybrid face robot should be adapted accordingly for use in South India to maximize long-term user engagement and compliance.Emotion recognition experiments with healthy older adults and PwD aimed to assess cultural appropriateness of the hybrid face robot’s simulated facial expressions. Recognition rates of human pictures were similarly high for PwD and HC for all emotions except for afraid, which was well recognized by HC but showed an accuracy below 50% for PwD. We found accuracies for all robot’s simulated facial expressions were lower than expected (between 14 and 62%), with similar values for both PwD and HC. Afraid, angry and disgusted expressions showed the lowest accuracies (between 14 and 20%) for both testing cohorts. Emotions with subtle differences such as surprised and afraid were regularly transposed in user perception. The major difference between the two control groups was observed for the happy expression: double recognition value was obtained for HC. Hence, a discrepancy was observed between cultural recognition of human emotions vs. robotic simulated expressions, however both PwD and healthy older participants perceived the robot’s facial representation of emotion comparably. Results from recognition of robot’s simulated emotions in Chennai, India are in contrast to the high emotion recognition rates obtained with healthy, younger participants in the United Kingdom  network connection, which resulted in lags and distortion of voice during remote human-robot sessions; 2) dependency of same network for clinician and PwD; 3) problems in streaming music; 4) lack of a synthetically generated robot’s voice instead of a recognizable human one, which may interfere with participants’ acceptability of the robot. As observed by the nursing assistant, these technical issues often resulted in distraction, impacting participant’s engagement, yet the advantages of robot-assisted cognitive engagement with PwD were acknowledged. The caregiver reported a positive impression of using the hybrid face robot as a telemedicine tool for cognitive engagement and perceived it as a technology to help with her husband’s condition. The clinicians who conducted cognitive engagement sessions commented that the use of affective robotic platforms for engaging persons with dementia, who otherwise are unable to participate in many activities due to the restrictions imposed by pandemic scenarios, holds significant promise. Further work will be necessary to identify factors that will facilitate the use of robotic platforms as a means of telemedicine and develop methods to overcome potential barriers.Overall, our results demonstrate remote cognitive engagement is feasible with PwD in India using the hybrid face robot as a telemedicine tool. The user-centred design and testing procedure followed with 14 PwD and 26 older adults interacting with the robot, in addition to repeated trials of remote cognitive engagement with one PwD through repeated sessions, provides a basis for deployment with larger participant cohorts. The robotic system may be used as an alternative platform to assist clinicians and support dementia care, which may be especially useful in times when social and medical support of PwD is limited, such as during and beyond the COVID-19 pandemic.We have introduced a multimodal affective robotic framework to enhance engagement in HRI with capacity to deliver robotic telemedicine to support mental health and dementia care during and beyond the COVID-19 context. We summarize the main findings of the study, their implication for future research and larger scale telemedicine deployment. We also outline the limitations of our investigation and highlight future directions.At a time of unprecedented overwhelming of global health systems in face of the COVID-19 outbreak, limited social and medical support is delivered to older adults and people living with dementia, who face greater isolation than ever before. Social robots hold significant promise to support mental health and may provide end-users with complementary assistance to stimulate interaction, alleviate anxiety and loneliness, in addition to reducing the caregiver burden, which is a critical need during and after the COVID-19 context. While user trust, complexity and expense of socially assistive robots is a challenge in any setting, we believe there is a larger gap of both resources and targeted research in LMICs. Cultural differences—which influence compliance—as well as technical challenges and cost need to be addressed. In this work, we make progress toward these challenges. In summary, contributions of this investigation include: 1) the robot’s software design optimization; 2) emotion modeling; 3) integration of autonomous conversation capability; 4) testing of the multimodal robotic system with healthy participants in the United Kingdom; 5) validation of the modified robot and its telemedicine interface with older adults with and without dementia in the cultural context of South India.Robotic Telemedicine for Mental Health Support). The user-centred procedure followed with 14 PwD and 26 healthy older adults interacting with the robot in South India, in addition to a set of repeated cognitive engagement pilot sessions with one person with dementia, provides a strong foundation for subsequent clinical use.Our study demonstrates feasibility and cultural appropriateness of robotic telemedicine for mental health support in India. One of the major findings of our study is that cultural adaptation of a social robot is critical—we propose a user-centred procedure that may be followed for successful introduction of a new affective robot in different cultural backgrounds, which involves iterative adjustments based on a set of validation experiments with target users . More specifically, accuracies above 90% were obtained for happy, tired, sad, angry, surprised and stern/disgusted robotic simulated facial expressions. When separated, stern and disgusted were occasionally mistaken for one another  but were easily distinguishable from all other simulated emotions. Furthermore, we have ported the entire robotic system to an inexpensive tablet platform. This highlights the flexibility and adaptability in design of the hybrid face robot, which we have identified as a key feature for cultural usefulness in India. By integrating the robot’s facial expressions with an autonomous conversational engine, we demonstrated real-time adaptable emotion of the robot in response to users’ speech in HRI experiments with healthy participants in the United Kingdom. Although participants did not interact with the robot with different modalities , there was a strong user preference for multimodal over pure voice communication.We optimized the software design and control system of a hybrid face robot comprising an animated digital face that simulates facial expressions based on mathematical affect space emotion mapping with a 3D faceplate to convey realism and depth. This led to considerably higher emotion recognition accuracies than earlier implementations of this style of robot . In our set of user-centred validation studies, including focus group discussions with stakeholders and emotion recognition experiments with 14 PwD and 26 healthy older adults, we identified the hybrid face robot as a feasible, culturally appropriate, and low-cost telemedicine system to support mental health in India. Additionally, we have piloted repeated sessions with one person with dementia as a test of the infrastructure to deliver cognitive engagement in regular sessions. Finally, we have proposed a protocol to introduce the robot for use with PwD and acclimatize the participant to the robot which, through repeated sessions, was received favourably by the participant in experiments, paving the way for further use.While our investigation of human-robot multimodal interactions with healthy participants in the United Kingdom yielded promising results, the AI voice system would need to support regional languages for fully autonomous use in India. Hence, we have designed an alternative test infrastructure to deploy the hybrid face robot as a telemedicine interface to deliver cognitive engagement in regular sessions  is that both PwD and clinician are required to be connected to the same internet network. We identified lags and distortion of voice during remote clinical sessions as the main technical issue to solve for next trials, in order to ensure maximum engagement. Although the nursing assistant indicated distraction of PwD when technical issues occurred, the participant was overall attentive and enjoyed interacting with the robot. Future experiments could quantify engagement with the robot, with more participants, different types and stages of dementia. Furthermore, for a more direct and rigorous assessment of cultural differences in recognition of robot’s simulated emotions, stricter controls would be needed for subject age, experience with interactive technologies, and cognitive ability. Education level of participants, which may impact acceptability and compliance, could also be used as a metric to be monitored in larger testing cohorts. Future clinical trials and wider deployment could also include end-user training sessions to fully judge the system capability, which may improve its performance.One fundamental limitation of the pilot study conducted in India using the robotic telemedicine interface was that only one person with dementia participated. These experiments were logistically very challenging; one of the major drawbacks identified was the screening of patients due to the resources and time available. The main limitation of the experimental setup created for remote cognitive engagement , and a trend of longer duration of engagement with the robot was observed through our protocol to introduce the robot to people with dementia in the cultural context of South India. Moreover, clinicians, PwD and caregivers indicated strong promise in the use of this social robotic platform as a means of telemedicine for dementia support in India. Hence, we propose it as an alternative or complementary technological solution to deliver cognitive engagement and enhanced mental health support to older citizens or PwD, during and beyond COVID-19. Plans for deployment in telemedicine sessions specifically motivated by the pandemic are currently underway.


It is generally accepted that tinnitus develops after peripheral hearing loss and is associated with altered auditory processing. The thalamus is a crucial relay in the underlying pathways that actively shapes processing of auditory signals before the respective information reaches the cerebral cortex. Here, we review animal and human evidence to define thalamic function in tinnitus. Overall increased spontaneous firing patterns and altered coherence between the thalamic medial geniculate body (MGB) and auditory cortices is observed in animal models of tinnitus. It is likely that the functional connectivity between the MGB and primary and secondary auditory cortices is reduced in humans. Conversely, there are indications for increased connectivity between the MGB and several areas in the cingulate cortex and posterior cerebellar regions, as well as variability in connectivity between the MGB and frontal areas regarding laterality and orientation in the inferior, medial and superior frontal gyrus. We suggest that these changes affect adaptive sensory gating of temporal and spectral sound features along the auditory pathway, reflecting dysfunction in an extensive thalamo-cortical network implicated in predictive temporal adaptation to the auditory environment. Modulation of temporal characteristics of input signals might hence factor into a  Tinnitus is frequently described as hearing a sound without an external source or as a ringing in the ears  and non-primary auditory cortices (non-PAC), as well as limbic regions Møller . The IC The MGV forms the “core” subdivision of the MGB. The MGV has a pronounced tonotopic organization, narrow tone frequency tuning, and exclusively responds to auditory input  and frequency-modulated (FM) sine tones as well as to natural calls  channels. The threshold to elicit a LTS is approximately 10 mV lower  than for classical action potentials , low threshold spikes (LTS) are important voltage dependent conductance mechanisms for thalamic relay cells  in anesthetized rats, while tinnitus was induced by sodium salicylate  seems to be reduced in persons with tinnitus. In addition, there is increased connectivity between cingulate cortices, likely the IFG and posterior cerebellum, which indicates changes in the function of a widespread network due to disrupted thalamo-cortical functional connectivity Fig. . A recenCurrently, there are no invasive human MGB recordings available, but a limited amount of case studies performed intracranial cortical recordings in patients that also experienced tinnitus, which can be linked to alterations in the MGB. Two case studies investigated persons with tinnitus, while performing intracranial recordings from the (secondary) auditory cortex . Results from one study in a person suffering from severe tinnitus for 14 years showed increased gamma and theta activity in one of the eight implanted electrode poles . HoweveAnother approach suggests that distorted firing patterns and altered oscillatory coupling mechanisms at the level of the MGB may induce tinnitus in a bottom–up fashion  has been associated with reduced neural activity for predicted information  and increased activity for unpredicted information  (Grunwald et al. Tinnitus has previously been associated with predictive coding (De Ridder et al. It is possible that there is a direct input route for auditory sensory processing to the cerebellum, as suggested by an ALE meta-analysis by Petacchi et al. . In addiBased on the limited number of studies investigating MGB functioning in tinnitus pathology and their overall heterogeneous approaches, it can be concluded that tinnitus is associated with increased spontaneous firing in the MGB, decreased functional connectivity between the MGB and a widespread thalamo-cortical network, in addition to decreased connectivity between the MGB and auditory cortices. Decreased functional connectivity between the MGB and auditory cortices can lead to reduced inhibition at the level of the auditory cortex. Parallel increased functional connectivity between the ACC and the IFG and the MGB may represent dysfunctional attentional processes or allostatic mechanisms. Similarly, altered patterns of oscillatory activity have been observed between the MGB and cortical areas, mainly expressed as increased activity in high-frequency gamma and beta bands, decreased activity in delta bands, and altered theta and alpha coherence, providing support for the thalamo-cortical dysrhythmia hypothesis. However, the existence and contribution of several local sub-networks to the development and maintenance of tinnitus, as suggested by Sedley et al. , should


Clinical outcomes after pathologic infection are variable in infected individuals, ranging from no symptoms, moderate symptoms, hospitalization, and even death. This outcome diversity is attributed not only to the virus itself but also largely to each person’s genetic/epigenetic characteristics. Inter-personal genomic/epigenomic variations and the resulting differences in gene expression profiles determine the process of infection as well as its clinical manifestation. Therefore, understanding the complexity of host–pathogen interactions and their effect on gene expression is imperative to develop treatments and prevent future infectious diseases.Over the last two decades, non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and the resulting phenome. This new knowledge has shifted our conventional concept of classic ncRNAs (such as tRNAs and rRNAs) that are constitutively expressed and play an invariable role in translation, which is a fundamental biological process. Fueled by the development of next-generation sequencing technology, a sensitive and high-throughput tool that captures a myriad of transcripts, researchers are now intensely studying various types of regulatory ncRNAs.At the crossroad of infectious diseases and regulatory ncRNAs, we arranged this Special Issue entitled “Non-coding RNAs in Pathogen-Host Interaction” and have compiled eight fascinating papers that cover clinically important pathogens and scientifically interesting ncRNAs. A brief outlook of these individual papers follows below.Pathogens covered in this Special Issue are mostly viruses, although a review paper by Morishita et al.  has alsomiRNAs and long ncRNAs are the two main groups of regulatory ncRNAs. In this Special Issue, Morishita et al. summarize the role of miRNAs in hepatic immunology  while AfThe works presented within this Special Issue represent endeavors to understand the cross-talk between ncRNAs and pathogen infection. As our knowledge about their interaction expands and deepens, we will move one step closer to subduing infectious diseases and potential future pandemics.