Uveitis is one of the most common manifestations of juvenile idiopathic arthritis (JIA). Currently, JIA is associated with decreased gut microbiota diversity. Studies confirm that perinatal events can cause aberrant microbial colonization. The objective of this study is to determine if JIA is associated with perinatal events with a secondary focus on these variables to the development of JIA-uveitis. 369 patients with strabismus (n = 200) or JIA (n = 196) were included in the study. Completed surveys  collected data about birth route, pregnancy and labor complications, JIA medications, and the presence of eye disorders. Analysis indicates that there is no relationship between JIA development and the perinatal events investigated. Similarly, no significance was found between JIA-uveitis and birth route or labor complications. Pregnancy complications, namely gestational diabetes (GD), were statistically higher in the JIA group with uveitis compared to JIA without uveitis. The data from this survey study showed that JIA-uveitis was highly associated with pregnancy complications, particularly with GD. However, no statistically significant association was found between JIA and route of delivery, labor complications, or pregnancy complications. Further studies are needed to understand the ways that GD interrelates with the development of uveitis in JIA patients. The autoimmune disorder can manifest with symptoms of joint pain, stiffness, inflammation within joints, and an overall sense of malaise. In addition to its rheumatologic symptoms, JIA exhibits ocularimplications where uveitis—an inflammation of the middle layer of the eye—serves as one of the most common extraarticular manifestations3 with arthritic symptoms typically preceding the development of uveitis1.Juvenile idiopathic arthritis (JIA) is the most common arthritic affliction within the pediatric population4 with the co-occurrence of these disorders predicting a poor overall prognosis2. Although well documented as a common co-occurrence with JIA, the pathogenesis, etiology, and predisposing factors of JIA-uveitis remain unclear5. As such, the central objective of this investigation is twofold: first, to uncover factors, specifically perinatal, that are linked to the development of both JIA and JIA-uveitis, and second, to lay the foundation for subsequent investigations into the underlying cause of this condition.Patients with JIA associated uveitis (JIA-uveitis) often require long-term immunosuppression and close follow-ups12, JIA demonstrates a correlation with microbiota dysbiosis which plays a vital function in conferring host immunity13. Particularly noteworthy is the reduced concentration of four types of short-chain-fatty-acid-producing bacteria15 within the gut microbiota of JIA patients. This reduction in bacterial diversity potentially triggers an altered immune response to the microbiota, contributing to the augmented circulation of auto-antibodies16. Although not innately pathogenic, these findings of auto-antibody production offer insight into the potential mechanisms that underlie the developmentof JIA.Much like several other autoimmune disorders4. Despite existing research, there remains to be a significant research gap pertaining to CS delivery, perinatal complications, and the subsequent development of JIA or JIA-uveitis.Perinatal events, including cesarean section (CS) deliveries and complications during pregnancy or labor are known to modify the microbiotic diversity of an infant. In contrast to vaginal delivery, CS delivery does not facilitate the transmission of maternal microbiota to the child, preventing bacterial colonization and growthThus, the objective of this study was to determine the presence of an association between these variables. In addition to investigating the risk of JIA development with CS delivery, this study also encompasses the examination of other perinatal factors, including complications during pregnancy and labor (Supplementary table).Out of the 396 patients meeting inclusion criteria, 200 were included in the strabismus group and 196 in the JIA group. Responses were received from 56 patients via mail—18 from the strabismus group and 38 from the JIA group. Respondent data were categorized based on initial grouping: JIA  and strabismus . Demographics and pathologies collected from each cohort are listed in Tables p-values for JIA development relative to birth route, pregnancy complications, and labor complications, using the strabismus group as reference. However, no statistical relationship were observed across the variables measured .Among JIA-uveitis patients with pregnancy (n = 6), gestational diabetes affected 50% of patients (n = 3). This was statistically significant compared to JIA patients without uveitis and experiencing gestational diabetes, as shown by chi-square analysis . The link between RA and maternal smoking found in this study may suggest a link between other forms of autoimmune diseases, such as JIA, and maternal smoking as well.Environmental factors such as maternal alcohol and nicotine use as well as TORCH infections have been known to disrupt fetal development resulting in various birth defects and lowered health outcomesAlthough our study did not establish a direct relationship between pregnacy complications and JIA development, there was a positive association between gestational diabetes (GD) and uveitis within JIA patients, potentially suggesting a correlation between these factors. Surprisingly, the effects of GD were confined to its influence on uveitis in JIA patients, with no overall relationship to JIA development.34. The adverse outcomes associated with GD can increase lifetime risk of obesity as well as cardiometabolic diseases35. Changes in adiposity observed with children born of GD contribute to the increased risk of lifetime obesity in these patients39. Babu et al.35 found that obese mothers are more prone to present with GD during pregnancy which, through a process of hyperglycemia-induced fetal programming, is associated with increased neonatal adiposity37. Muhammed et al.’s39 experimental studies indicated that increased fat composition exacerbated autoimmune uveitis in mice models. This was due to the release of proinflammatory mediators with targeted ocular antigens coupled with decreased regulatory immunity that is associated with white adipose tissue28. However, a more direct analysis of the association between GD and uveitis would be needed to understand the mechanism for this relationship.Children born with GD have an increased risk of adverse perinatal outcomes including hypoglycemia, macrosomia, and birth traumaA significant constraint of this study lay in the diminished response rate which, consequently, led to a small sample size and reduced statistical power. Although most variables analyzed indicated a broad range, the study lacked racial diversity with very few non-white respondents. This is an inherent disadvantage of survey studies with little means of improvement. The study’s sample group exhibited a substantial homogeneity in terms of its size and composition, highlighting the necessity to validate the findings through subsequent research before extending them to a broader population. Nevertheless, the study provides the framework and preliminary results that can guide future studies.This was a survey-based study including patients diagnosed with JIA, while patients diagnosed with strabismus constituted the control group, selected for comparable age and lack of immunologic association. Inclusion criteria were pediatric and adult patients with a diagnosis of either strabismus (control) or JIA at the Indiana University Health System . Eligible patients were sent surveys via mail, with instructions to return them using the provided prepaid envelope. Information about the study was disclosed in the initial surveys with declaration that the return of the survey constituted as informed consent for participating in the study. This study adhered to the Declaration of Helsinki and was approved by the Indiana University Institutional Review Board.Participants were categorized into two cohorts based on initial inclusion diagnoses. For respondents with strabismus collected data included sex, date of birth, race/ethnicity, birth route, whether C-section was medically recommended or elective, gestational age at birth, complications during pregnancy, and complications during labor Similarly, data collected from returned surveys of the JIA group included information about sex, date of birth, race/ethnicity, age of JIA diagnosis, medication for JIA, presence of eye disorders, birth route, whether C-section was medically recommended or elective, gestational age at birth, complications during pregnancy, and complications during birth. A comprehensive list of the data collected from each survey can be found in supplementary data. Participant responses were gathered through the surveys and recorded electronically for data consolidation.The survey employed a combination of free response, binary (yes/no), and multiple-choice questions. Binary questions addressed sex, birth route, and whether C-section was medically recommended or not. Multiple choice questions were utilized for pregnancy complications, labor complications, JIA medication, race/ethnicity, and eye disorders. Participants selecting ‘other’ were prompted for further details in their responses. Questions requiring further elaboration or those that were challenging to categorize were managed through free responses. Date of birth, gestational age at birth, and age of JIA diagnosis were collected through free response questions.A qualitative approach was adopted to address responses necessitating further elaboration. Responses specifying medication names and complications during pregnancy or labor beyond questionnaire options underwent preliminary analysis to ensure comprehensiveness. These responses were then quantified for frequency and type during analysis.Descriptive analysis was applied to determine median and mode age for diagnosis and gestational age at birth. A binary methodology was used employed to calculate the occurrence of all other variables. Correlation between the variables of interest was assessed using chi-square analysis, as well as Fisher's exact test for smaller cell samples .Our investigation revealed no relationship between JIA and birth route, pregnancy complications, or labor complications, although the constrained respondent count limits data interpretation. In addition, JIA-uveitis cohorts demonstrated minimal association with variation in birth route and labor complications. However, pregnancy complications, namely gestational diabetes, showed statistical significance in uveitis development within the JIA patient population. In sum, these findings offer valuable insights into the plausible causal link between JIA patients born of gestational diabetes and uveitis. Subsequent research endeavors are needed to validate this relationship and uncover potential underlying mechanisms.Supplementary Table 1.


The climate crisis calls for urgent action from every level of the US healthcare sector, starting with an acknowledgment of our own outsized contribution to greenhouse gas emissions (at least 8.5% of carbon emissions). As the climate continues to become warmer and wetter, the medical establishment must deal with increasing rates of pulmonary and cardiovascular diseases, heat-related illness, and emerging infectious diseases among many other health harms. Additionally, extreme weather events are causing healthcare delivery breakdown due to physical infrastructure damage, slowed supply chains, and workforce burden. Pathways for healthcare systems to meet these challenges are emerging. They entail significant measures to mitigate our carbon footprint, embrace shared and equity-driven governance, develop new metrics of accountability, and build more resilience into our care delivery processes. We call upon SHEA to play a unique leadership role in the fight for sustainable, equitable, and efficient health care in a rapidly changing climate that immediately threatens human well-being. Significant morbidity and mortality are directly and indirectly associated with climate-driven weather, especially extreme temperatures, tropical and coastal storms, and wildfires. A recent WHO report further indicated that well over 95% of people on Earth are exposed to poor air quality, and air pollution is now counted among the greatest causes of mortality worldwide. With ongoing high levels of fossil fuel combustion, cascading harms to environmental and human health are happening right now and will worsen in the near future. Furthermore, the damages are neither equally nor equitably distributed; they disproportionately affect the most vulnerable and least resilient populations among us: children, the elderly, ethnic minorities, poorer communities, and those with underlying health problems. Accordingly, the WHO declared in 2021 that climate change represents “the single biggest health threat facing humanity.” The calamity cannot be overstated. The IPCC6 has identified a 1.5°C rise in global temperatures over preindustrial levels as a tipping point at which widespread degradation of human and natural environments will be “impossible to reverse.” Having already exceeded 1.2°C of warming, a new UN Environment Programme report indicates that there is now “no credible pathway” to keep the rise in global temperatures below the key threshold of 1.5°C. Based on current levels of fossil fuel use, we are on track to exceed 2.5°C by the end of this century. Widespread harm to individual and public health, magnified by the rapid pace of climate change, is expected to accelerate, with the potential to overwhelm healthcare services worldwide  have allowed for unprecedented human achievements and powered the modern economy, but at the same time it has promoted the 2 main drivers of climate change: air pollution and atmospheric accumulations of carbon dioxide and other greenhouse gases (GHG). Dramatic increases in land and ocean mean surface temperatures, rising concomitantly with carbon emissions over the past 150 years, have led to novel weather patterns characterized by intense storms and flooding, extreme heat waves, and unpredictable cycles of prolonged drought and torrential rainfall. The undeniable evidence for these effects is laid out in the most recent report from the Sixth Intergovernmental Panel on Climate Change (IPCC6), published in the fall of 2021, which represents a consensus of 270 authors from 67 countries. Efforts to reduce that contribution are underway, prompted by proactive institutions across the country, but they need to expand dramatically and quickly. At the same time, we are challenged to understand and adapt to the climate-induced health threats to individuals and populations, while maintaining high-quality care delivery, even as the climate crisis rapidly unfolds. Herein, we propose that preparing for a harsh and unpredictable climate future starts by reimagining a healthcare system founded on foresight, planning, and resilience.The climate crisis calls for urgent action from every level of the US healthcare sector. First, we must acknowledge the impact of our own carbon footprint: the healthcare sector is among the most carbon-intensive services in the world and contributes significantly to global greenhouse gas emissions.2) equivalent (GtCO2e) emissions or 4.4% of the total emissions from these nations. The countries studied represented 54% of the world’s population and 78% of world GDP, demonstrating the extensive impact of healthcare activities on global emissions. Put simply, if the healthcare industry was a country, it would be the fifth-largest greenhouse gas emitter on the planet.In 2014, an in-depth global study examined all Organization for Economic Cooperation and Development (OECD) countries (minus Chile), plus India and China, was the first to show that the healthcare sectors from the 36 countries combined were responsible for 1.6 gigatonnes of carbon dioxide  in 2018. Ironically, while the healthcare sector is positioned on the front lines of the climate crisis, coping with an array of climate-related illnesses, it is also a significant contributer to the actual cause of that crisis.A second, more comprehensive study of global health-sector emissions, also using 2014 data, was conducted by Healthcare without Harm (HWH), which is an international NGO working to transform the health sector worldwide into an ecologically sustainable enterprise. In the United States, exteme heat is the deadliest weather-related hazard. Heat-related mortality rates have been rising in recent years with escalating frequency and duration of brutal heatwaves stemming from the warming effects of 200 years worth of accumulated greenhouse gases. Infectious diseases due to emerging and re-emerging pathogens are increasingly recognized as an important indirect consequence of anthropogenic climate change. These can be categorized as (1) “spillover infections,” primarily viruses that are derived directly from animal or, most often, bat sources; (2) vectorborne infections transmitted by arthropod vectors such as ticks and mosquitoes; and (3) bacterial infections (as well as other infections) emerging as a consequence of changing climatic conditions.The wide range of health harms posed by climate change vary by geography, emissions sources, population vulnerability, and regional or national adaptability and resilience. Air pollution is by far the most significant and widespread climate threat across the globe, with >7 million people a year dying from exposure to outdoor air pollution primarily caused by burning fossil fuels: 1 in 8 of all deaths globally. Waves of human outbreaks due to viruses that were originally established in wild or domestic animal reservoirs have been observed in the early 21st century: Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), the 2009 pandemic influenza H1N1, and the COVID-19 pandemic are prominent examples.Spillover infections, primarily due to viruses, are those that occur naturally in animals but, due to population movements of both animals and humans, have “jumped species” and have become capable of causing human infections. As the Earth warms, especially in equatorial regions, animal and insect vector species seek cooler habitats in more temperate zones north of the equator or at higher altitudes. At the same time, people are moving toward these same regions, seeking refuge from rising sea levels and punishing cycles of heat, drought, and flooding. Demands for increased food production intensify with the growing human population, leading to damaging land-use policies that are linked to emerging zoonotic diseases. Deforestation to clear land for agricultural and ranching purposes destroys natural habitats, forcing wildlife (and their pathogens) into more populated areas. The sum of these human activities is an expansion of opportunities for spillover viruses from animal sources.Climate change and rapid human population growth are the intertwined problems that drive this spillover trend. Both promote intensified contact between human beings and animal reservoirs, enhancing opportunities for pathogens typical in animal and insect vectors to become invasive to human populations. has indicated that “This ecological transition may already be underway, and holding warming under 2°C within the 21st century will not reduce future viral sharing.” Bats, they added, account for the majority of novel viral sharing due to their widespread global distribution and their ability to host a variety of viruses.Modeling by Carlson et alEbola virus disease is perhaps the most notorious example of a spillover virus. Close associations between the wild animals that host Ebola, primarily nonhuman primates and bats, and people who hunt and eat them , or encroach on their habitats by forest destruction and urbanization, allow for the jump from animals to humans. Periodic human outbreaks in endemic regions of sub-Saharan Africa as well as in nonendemic areas of the globe—have heightened public health conerns about broader Ebola outbreaks in human populations as spillover conditions accelerate.Aedes aegypti, the principal mosquito vector of many arboviral diseases including dengue, chikungunya, yellow fever, and Zika, has spread globally in recent decades, potentially exposing almost half of the world’s population to these diseases. Dengue virus has extended it range well beyond its traditional tropical and subtropical geography in the 21st century, with transmission and outbreaks seen in parts of the United States, southern Europe, South America, and Australia. Chikungunya (2013) and zika (2015) infections also surprisingly emerged in temperate regions in the Americas. Warming temperatures, as well as both excessive rainfall and drought conditions, play a critical role in the optimal development, lifespan, and disease transmission capabilities of Aedes mosquitoes. Comparably, robust data suggest that long-term range expansion has been occurring for the Anopheles mosquito vectors of malaria in Africa over the last century. The establishment of mosquito vectors at higher elevations (documented in both Africa and South America) and into more temperate zones, farther from the equator, will likely drive the expansion of malarial disease in those regions. Awareness of these geoclimatic alterations is essential in diagnosing arthropod-borne infections in patients coming from regions not traditionally considered endemic.Arthropod-borne infections are increasing worldwide, and this expansion is attributed to a combination of increased urbanization, global travel, and environmental changes. Specifically, warming temperatures and increased precipitation trends that favor vector reproduction, feeding, and location play a large role.Borrelia burgdorferi) are the 2 most prevalent vectorborne diseases. Both were initially reported in the northesastern United States in the late 20th century, their epidemiological “march” westward. This pathogenic success is owed to warmer and wetter weather patterns that promote the survival and range expansion of their vectors, Ixodes spp ticks and Culex spp mosquitoes. West Nile Virus has an especially significant endemic presence in the United States since its introduction from Europe to New York in 1999. Sporadic cases as well as larger outbreaks occur each summer, scattered geographically across the country, depending on local conditions that support Culex mosquito populations. In the summer and fall of 2021, the largest identified single West Nile outbreak in US history  occurred in southwestern Arizona, linked to wetter-than-average rainfall.In the United States, West Nile virus fever (WNV) and Lyme disease  platforms could reduce the need for starting empiric antibiotics or antivirals but are typically costly. However, the high expense and uneven availability of such tests, especially in smaller and more rural hospitals, are likely to complicate such stewardship pressures. Antibiotic resistance in bacteria develops largely under the selective pressure of antibiotic use and is then spread person to person. Other factors, however, may contribute to population-level increases in antibiotic resistance including, for example, the overuse of antibiotics in livestock farming. In a 2018 study published in Nature Climate Science, McFadden et al explored the role of climate  and other factors on the distribution of antibiotic resistance in human infections across the United States. In a data set of 1.6 million infections due to Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus, they identified significant associations between antimicrobial resistance patterns in these common pathogens and higher local minimum temperatures. Another recent study similarly showed modest but significant impacts of both local temperature and humidity on surgical-site infection (SSI) rates within a representative data set in the continental United States, 2007–2014.The connection between emerging and re-emerging antibiotic-resistant bacterial infections and climate change is less well defined, although there are supportive lines of evidence.Locoregional maximum daily precipitation and humidity, and minimum daily temperature were all significant predictors of SSI diagnosed after discharge. Climate modeling in this report further showed that small but meaningful increases in postdischarge SSIs can be anticipated over the next several decades if overall carbon emissions are not significantly reduced, with the Southeast region being particularly vulnerable. The broad epidemiologic associations in these reports do not imply causality, of course. However, they suggest that greenhouse-gas driven increases in ambient temperatures (and humidity in the study of SSIs) probably contribute to the rising prevalence of common hospital pathogens in the United States, including antibiotic-resistant strains. The implications are notable for infection control practitioners. Increased mortality in newly treated TB patients has also been linked to breathing higher concentrations of air pollution components  in a recent Chinese study. Wildfires represent a significant cause of exposure to ambient air pollution in the United States and are increasingly frequent due to climate change. Wildfire smoke is laden with particulate-matter lung irritatants, PM2.5 and PM10, that may exacerbate pulmonary diseases, including tuberculosis. This concern was affirmed in a recent study of patients with active tuberculosis disease from 8 California counties between 2014 and 2019  in which wildfire-associated events, as determined by particulate matter monitoring across the regions, were associated with 23% higher odds of tuberculosis diagnosis over a 6-month observation period. This finding should prompt practitioners to consider wildfire air pollution as a risk for active tuberculosis disease in the United States.Exposure to air pollution poses a well-documented increased risk for the development of tuberculosis in endemic regions.Vibrio cholerae growth. The WHO recently reported that a global surge in cholera outbreaks over the past was “unprecedented,” with more frequent, larger, and more deadly than in years past. They appear related to major floods, unprecedented monsoons and cyclones promoted by climate change, combined with the known risk factors of poverty, clean water scarcity, and inadequate sewage handling and water treatment. Other waterborne diseases  including leptospirosis, hepatitis A, cryptosporidium, norovirus and other diarrheal pathogens, are anticipated become more prevalent worldwide as a consequence of climate-change hazard risks combined with sociodemographic trends of urbanization, poverty, overcrowding and mass human displacement due to natural disasters and conflict.Cholera disease is predictably magnified by warmer and wetter climatic conditions that favor N. fowleri), and the fungi Candida auris and Cryptococcus gattii, have emerged or re-emerged in recent years, and some evidence links them to altered climate patterns. These unusual pathogens are typically more difficult to diagnose and may be intrinsically resistant to common antimicrobials.Nonbacterial infections such as primary amebic encephalitis  infections globally. The medical sector failed to plan for workforce stresses and shortages, communication fiascoes, and supply-chain breaches that complicated care delivery. Thus, while the COVID-19 pandemic revealed an unexpected level of fragility within the American healthcare system, climate-related events compounded the issues of being unready. These cumulative failures should now swiftly translate into lessons for the healthcare sector, stimulating preparations to build resilience and redundancy into existing systems. Preparedness plans are necessary not only to meet the challenges of a next pandemic but also to address the immediate and near-future health impacts incurred by the current climate crisis.In the United States, concomitant climate-driven natural disasters further compromised healthcare access and delivery at the height of the pandemic: a deadly heat wave in the Pacific Northwest in 2020 and 2021; catastrophic floods in California and Louisiana; a deadly freeze event in Texas causing widespread days-long losses of power and water; and violent storms and tornados across the country all may have contributed to excess morbidity and mortality within COVID-19–stressed healthcare facilities. In this context, SHEA is uniquely positioned to actively participate in partnerships that are developing pathways to healthcare resiliency. SHEA’s history and impeccable reputation for advancing the science of healthcare epidemiology—and translating that knowledge into effective policy and practice—would bring invaluable strengths to the all-hands-on-deck approach needed to address climate change  regulations requiring that facilities adopt emergency management programs and plans. The CMS identified 3 key essentials maintaining access to healthcare during disasters or emergencies: safeguarding human resources, maintaining business continuity, and protecting physical resources. CMS expanded their concerns in the recent Fiscal Year 2023 Inpatient Prospective Payment System proposed rule (August 2022), in which feedback was sought on how to maintain uninterrupted patient services due to climate threats and catastrophic weather events, with particular attention to underserved populations that are disproportionately harmed by climate change. Additionally, they urged the broader healthcare sector to evaluate and reduce its outsized contribution to greenhouse gas emissions.https://www.hhs.gov/climate-change-health-equity-environmental-justice/climate-change-health-equity/actions/health-care-sector-pledge/index.html) which commits them to take an inventory of their carbon footprint and begin active mitigation. A leader in this effort is the Practice Green Health organization , which will guide member institutions through the carbon emissions accounting and decarbonization processes.Abundant information is available to guide assessments and planning for resilience in healthcare systems Box . PractitBox 2.Tool Kits for Creating Climate Resiliency in Healthcare SystemsSustainable and Climate Resilient Health Care Facilities Initiative (SCRHCFI) https://toolkit.climate.gov/topics/human-health/building-climate-resilience-health-sectorUS Department of Health and Human Services’ https://www.who.int/teams/environment-climate-change-and-health/climate-change-and-health/capacity-building/toolkit-on-climate-change-and-healWorld Health Organization (WHO) Smart Hospitals ToolkitPan American Health Organization’s Health Care Facility Climate Change Resiliency ToolkitCanada’s Climate Change and Health DiagnosticWorld Bank Group’s Creating climate-resilient health systems is critical, complex, and daunting because climate change is a problem with no clear boundaries. Its harmful effects are global, amplifying and stretching far into the future. Traditional healthcare emergency management practices cannot encompass the entirety of the threats it poses to human health and healthcare. Accordingly, a transformational process is required, one that engages healthcare practitioners and partners at every level and sector of the enterprise and is patient-centered and guided by equity and justice values. Institutional governance and leadership within healthcare systems must think and act quickly and creatively to make necessary changes. The scope of the planning, assessments, research, and programmatic activities to meet this challenge, coupled with the climate-driven emergence of infectious diseases, aligns well with the experience and expertise of those knowledgeable in healthcare epidemiology. The SHEA would be a natural association to host the comprehensive needs to create climate-resilient health systems.


Ghrelin is well known for its ability to control feeding, hunger, and metabolism. Moreover, ghrelin signaling appears central for alcohol-mediated responses; findings reviewed herein. In male rodents GHSR antagonism reduces alcohol consumption, prevents relapse drinking, and attenuates the motivation to consume alcohol. On the other hand, ghrelin increases the consumption of alcohol. This ghrelin-alcohol interaction is also verified to some extent in humans with high alcohol consumption. In addition, either pharmacological or genetic suppression of GHSR decreases several alcohol-related effects . Indeed, this suppression blocks the alcohol-induced hyperlocomotion and dopamine release in nucleus accumbens as well as ablates the alcohol reward in the conditioned place preference model. Although not fully elucidated, this interaction appears to involve areas central for reward, such as the ventral tegmental area (VTA) and brain nodes targeted by VTA projections. As reviewed briefly, the ghrelin pathway does not only modulate alcohol-mediated effects, it regulates reward-related behaviors induced by addictive drugs. Although personality traits like impulsivity and risk-taking behaviors are common in patients with AUD, the role of the ghrelin pathway thereof is unknown and remains to be studied. In summary, the ghrelin pathway regulates addiction processes like AUD and therefore the possibility that GHSR antagonism reduces alcohol or drug-taking should be explored in randomized clinical trials.Alcohol use disorder (AUD) is often described as repeated phases of binge drinking, compulsive alcohol-taking, craving for alcohol during withdrawal, and drinking with an aim to a reduce the negative consequences. Although multifaceted, alcohol-induced reward is one aspect influencing the former three of these. The neurobiological mechanisms regulating AUD processes are complex and one of these systems is the gut-brain peptide ghrelin. The vast physiological properties of ghrelin are mediated  In society harmful alcohol consumption is a global health problem, where alcohol use disorder (AUD) is a top pathology associated with this risky consumption . The heavia activation of growth hormone secretagogue receptor (GHSR), a receptor known for its intrinsic activity and ability to heterodimer with other receptors [for review see Cornejo et al.  exerts its physiological effects o et al. ]. The reo et al. . Ghrelino et al. . Notablyo et al. , 9. The o et al. ]. Ghrelio et al. ]. This rThe reviewed articles presented herein were selected by means of keywords and the included articles were quality checked before inclusion . As thisThe ability of GHSR antagonists to reduce alcohol drinking has been shown in numerous preclinical studies . It was In support for these initial findings where a decline in alcohol drinking after GHSR inhibition is reported, are additional studies demonstrating a beneficial role of GHSR antagonists on other alcohol drinking behaviors. One of these is relapse drinking after abstinence, a trait blocked by a GHSR antagonist in male mice  and malepre-pro-ghrelin gene are associated with aspects of the AUD diagnosis . Indeed, central, but not peripheral GLP-1 receptors appear to be important for the ability of a GLP-1 receptor agonist to attenuate alcohol-related responses in male mice .The decline in alcohol drinking by GHSR antagonists in animals exposed to long or short-term alcohol may be due to a reduction in alcohol’s rewarding experience as this also is reduced by GHSR antagonism . A featuper se  are enhanced by ghrelin and reduced by GHSR suppression, there are confounding factors that may influence the interpretation of these data. One such may be caloric intake and consummatory behaviors as these are well-established functions of ghrelin [for review see Espinoza Garcia et al. ]. This ah effect , 113. Sth effect , 115. Whh effect . HoweverAlthough these preclinical studies show that different GHSR antagonists have a similar ability to decline alcohol drinking, all but one study  are condAs reviewed above, ghrelin and its receptor appear central for alcohol responses. However, other substrates of the ghrelin pathway exist and their role in addiction processes is unknown. The ghrelin gene is translated into ghrelin-obestatin, which is converted to pro-ghrelin which after acylation by GOAT and conversion forms the active form of ghrelin; acyl-ghrelin (here denominated ghrelin) [for review see Muller et al. ]. GhreliIn conclusion, the vast number of preclinical studies reveal that the ghrelin pathway is central for reward, reinforcement and addiction processes. Besides, findings from these preclinical studies are accompanied with supporting studies in humans [for review see Morris et al. ]. When iEJ conducted the literature search for the present review article, summarized the work conducted within the field, and wrote the review.


Autism Spectrum Disorder (ASD) is highly heterogeneous across individuals, making it difficult to accurately diagnose and effectively treat each case. Genetics  participants of matching characteristics . These approaches work well in theory, but assume that shared sources of variation are few and known (because participants must be selected taking these sources of variation into account). However, brain anatomy is shaped by a multitude of genetic and environmental factors , but at the level of individual participants (as in case-control matching). Contrastive variational autoencoders  are designed for diagnosis using single aggregate scores; finer-grained measures might be needed to capture the multidimensional nature of ASD  or at least interpretable. A recent study went in this direction, predicting disease-specific brain aging without longitudinal data conditioning generative models using disorder and age information (Xia et al., Descriptive research into ASD biomarkers and subtypes must go hand in hand with intervention studies aimed at improving the quality of life in affected individuals. While there are various non-medical interventions available for ASD treatment (Bond et al., Individual differences are a key challenge in understanding biological bases of ASD and developing targeted treatments. The field can tackle this challenge by making concerted progress along several key research directions: improving the behavioral characterization of participants, integrating data modalities, modeling comorbidity, taking advantage of new computational techniques, and ultimately studying the link between individual variation and intervention outcomes. Across all these research directions, disentangling disorder-specific variation from unrelated variation will be an essential asset.AA and ES: conceptualization, research, and writing. SA: conceptualization, research, writing, funding acquisition, and supervision. All authors contributed to the article and approved the submitted version.


Critically ill patients presenting with acute on chronic liver failure (ACLF) represent a particularly vulnerable population due to various considerations surrounding the syndrome definition, lack of robust prospective evaluation of outcomes, and allocation of resources such as organs for transplantation. Ninety-day mortality related to ACLF is high and patients who do leave the hospital are frequently readmitted. Artificial intelligence (AI), which encompasses various classical and modern machine learning techniques, natural language processing, and other methods of predictive, prognostic, probabilistic, and simulation modeling, has emerged as an effective tool in various areas of healthcare. These methods are now being leveraged to potentially minimize physician and provider cognitive load and impact both short-term and long-term patient outcomes. However, the enthusiasm is tempered by ethical considerations and a current lack of proven benefits. In addition to prognostic applications, AI models can likely help improve the understanding of various mechanisms of morbidity and mortality in ACLF. Their overall impact on patient-centered outcomes and countless other aspects of patient care remains unclear. In this review, we discuss various AI approaches being utilized in healthcare and discuss the recent and expected future impact of AI on patients with ACLF through prognostic modeling and AI-based approaches.  AI applications are being increasingly utilized in healthcare. Hepatology is no exception. Recently, there has been a significant application of artificial intelligence (AI) methodologies to hepatology including radiomics, histopathology, predictive and prognostic modeling, and estimation of posttransplant outcomes.ACLF is a recently recognized syndrome and is associated with increased short-term mortality.In up to 40% of patients presenting with ACLF, no precipitating event is identified. Infection, in particular spontaneous bacterial peritonitis and pneumonia, has been deemed a common cause of ACLF and has been independently associated with mortality.Currently, multiple definitions exist for ACLF as outlined by the European Association for the Study of the Liver—Chronic Liver Failure (EASL-CLIF), North American Consortium for the Study of End-stage Liver Disease (NACSELD), and the Asian Pacific Association for the Study of the Liver (APASL) Table .16 TheseThe EASL-CLIF definition was developed using a cohort of patients with predominantly alcohol-induced liver disease and utilized a Chronic Liver Failure—Sequential Organ Failure Assessment (CLIF-SOFA) score, which was a prespecified modified Sequential Organ Failure Assessment (SOFA) score specifically developed for the purposes of identifying and grading ACLF.Prior prognostic scores used to estimate the degree of portal hypertension and qualify the severity of cirrhosis, Model for End-stage Liver Disease (MELD), Model for End-stage Liver Disease-Sodium (MELD-Na), Child-Turcotte-Pugh (CTP), among many, are likely not weighted properly to be meaningfully applied to ACLF specifically. Presumably due to the degree of inflammation present in ACLF, models incorporating scores detecting global organ dysfunction  have been shown to be superior to liver-specific models.The clinical course of ACLF in the initial days following the identification, that is, trajectory, likely has more prognostic value than the initial severity and might ultimately have a more meaningful impact when it comes to minimizing harm, limiting unnecessary cost, and improving end of life.Initially labeled by John McCarthy in 1955, AI is a nondescript term used to define a broad range of techniques that allow computers to perform tasks typically thought to require human reasoning and problem-solving skills.Beneath the umbrella of AI applications, machine learning (ML) encompasses various techniques including supervised ML, unsupervised ML, semisupervised learning, reinforcement learning, neural networks, and deep learning (DL). Supervised ML involves labeled input and output data which the algorithm then uses to create a mathematical model from as it “learns” relationships between input and output data. Supervised ML is a technique frequently used in healthcare. Labeled input data represent various aspects of patient-level data and labeled output data represent various desired or expected clinical endpoints. The algorithm itself interprets input data and relationships within data. Unsupervised ML allows the algorithm to extract features from unlabeled input data without output data in an exploratory nature and effectively allowing the data to “speak for itself.”Natural language processing is a technique that allows extraction of text from various data sources. In healthcare, this is typically used to extract text data and patient-level information which can then be utilized as input in other AI models.In recent years, there has been a significant increase in the application of AI to the fields of critical care and hepatology. This has coincided with significant advancement in AI methodology and computing power as well as the availability of large data cohorts. A recent review by Ahn et alA few recent studies in ACLF patients have effectively utilized AI approaches. Table p < 0.0001) demonstrating increased accuracy compared with common MELD-based scoring systems.Zheng and colleagues created and validated a model including patients diagnosed with HBV-associated ACLF by APASL criteria. Patients with causes of liver disease other than HBV were excluded from both the training and validation cohorts. Using ANN, patient-level modeling was compared with various MELD-based predictors of mortality with 90-day mortality as an outcome. In the validation cohort, authors reported an area under the receiver operating characteristic 0.765 . Given their improved accuracy and specificity to ACLF, these scoring systems may serve as comparators for future ML approaches, especially when evaluating 90-day mortality in patients with ACLF by APASL criteria.Shi and colleagues evaluated a large cohort of over 1000 patients with suspected ALCF due to HBV and created and validated novel classification and regression tree and logistic regression models that outperformed the traditional MELD score with the area under the receiver operating characteristic 0.896 and 0.914, respectively (In a methodological approach, Xu and colleagues utilized supervised learning techniques similar to small sphere and large margin and twin support vector machines to develop prediction models for ACLF patients with missing demographic and biochemical data and imbalanced mortality and survival outcome data. Models were then compared based on their ability to accurately predict mortality. Mortality prediction was then also correlated with MELD scores.These studies demonstrate the benefits of utilizing AI approaches for predictive modeling and other aspects of ACLF. When compared with traditional scoring systems there was improved prognostic accuracy. These approaches present tools for preparing and analyzing heterogeneous or incomplete data, which are common for ACLF patient-level data, with higher accuracy than the currently applied standards which were not created for ACLF patients. However, with the exception of the methodologic study conducted by Garcia and colleagues which included patients meeting EASL-CLIF criteria for ACLF, data to date are limited in scope to a predominantly HBV-associated ACLF cohort fulfilling APASL criteria. Further, the majority of the predictive models developed using AI approaches utilized an ANN which is a black-box approach. In the context of ACLF, AI approaches are especially subject to limitations related to such black-box approaches, biases in dataset creation, limited and heterogeneous data due to high short-term mortality, preexisting geographical cohort distributions, and minimal prospective data available for validation.When thinking about the near future, applying novel AI techniques to ACLF patient populations has the potential to shed light on treatment strategies, transform our current understanding of patient outcomes including organ transplantation, and even highlight previously unknown or misunderstood physiological and pathophysiological mechanisms.To date, we are unaware of data evaluating natural language processing or digital twins and other expert systems in patients with ACLF but data have demonstrated that expert systems can replicate and accurately estimate outcomes in diseases with complex underlying pathophysiology such as diabetes and sepsis.We anticipate that eventually these models can also be used for medical education and other training purposes and, with proper validation, to evaluate decisions in critically ill patients including those with ACLF without exposing patients to unnecessary risk.While AI, and, more specifically, expert systems will enable a more individualized approach to care, we must be mindful of ethical issues and address them before and as they arise. In North America and Europe, major oversight organizations have set regulations on AI applications but such applications in healthcare are a new phenomenon. With the rapid expansion of AI in healthcare, regulatory mechanisms remain limited in their scope especially when it comes to ML applications.Data privacy, including individual and institutional rights to health-related data, will require consideration. Availability of these technologies could also have ethical and societal implications due to discrimination and isolation of certain populations especially when it comes to the potential for training validation data sets with bias and subsequent resource allocation or decision support. As these technologies are developed, proper refinement and transparency will be required and during this process they should augment and supplement provider decision-making rather than replace it. Inevitably, decisions “influenced” by AI will have implications when it comes to allocation of responsibility and lines between algorithm-based decisions and clinician decisions will become further blurred. Questions regarding well-established ethical concepts such as patient autonomy, beneficence, nonmaleficence, and justice will inevitably arise.ACLF is a recently established syndrome associated with significant mortality. Current data are almost exclusively limited to predictive and prognostic models developed using traditional statistical approaches based on retrospective data. Modern AI approaches are increasingly being applied to ACLF and those previously developed for similarly complex disease processes can likely be applied to ACLF to enhance education and training as well as to aid decision-making. As with all new technologies and especially given the complexity of related decision-making, ethical implications, and methodologic considerations unique to these new approaches must be considered when applying AI to patients with ACLF.


Maintaining brain health and promoting precision neurology are endeavors with different perspectives but sharing the same goal of combatting brain disorders. Precision neurology is an off-shoot of precision medicine, an initiative announced by President Obama in 2015 to develop prevention and treatment strategies that take individual variability into account  can be affected in movement disorders, highlighting the need to consider the complex relationships between brain health and precision neurology in clinical practice, with individual variations across experiential domains potentially influencing both symptoms and treatment outcomes.For example, in this topic, Wang et al. for a patient with levodopa-resistant dopa-responsive dystonia with an atypical mutation illustrates the potential value of applying precision medicine in neurology—precision neurology.As this topic demonstrates, other studies are consolidating foundations for preventive and therapeutic advances in precision neurology, including genome-wide association studies (GWAS) and genome sequencing  that open the way for incorporating genetic variants into the diagnosis and prognosis of both rare and common neurological diseases and into clinical trials of therapeutic interventions based on the patient's genetic variants. The excellent treatment outcome by Xiang et al. suggests deficiencies in confrontation naming and semantic fluency reflect abnormal brain Aβ deposition, which may serve as a clinical red flag for brain health maintenance. The potential for precise early intervention is increasing with advances in monitoring Aβ and other biomarkers in biofluids at the pre-symptomatic stage  by ic stage .Hu et al. report on systematic problems, notably gastrointestinal, cardiovascular, urinary and sexual abnormalities, that can co-exist with movement disorders. The prevalence of comorbidity with brain disorders in the elderly underlines the value of both maintaining general wellbeing for brain health and considering causal directionality of comorbidities.Other organs contribute to brain health –12 and nDespite advances in neuroimaging and other technologies, neuropathology remains essential for correlating observations in living patients with neuropathological features essential for definitive diagnosis and subtype delineation in many neurological conditions, notable examples including neurodegenerative diseases and chronic traumatic encephalopathy , 16.If precision neurology and brain health are viewed as two sides of a coin, human brain banking is the edge that connects the two sides. Human brain banks are now being seen as core research facilities that support both clinical and fundamental researchers –18. BuilMaintaining brain health and consenting to become a brain donor are voluntary choices relying strongly on the willingness of participants. Complementing this, optimization of brain health requires correlating postmortem brain data with individual variations interrogated by precision neurology, studies resting largely on contributions from clinical and research professionals and encompassing individual behaviors, lifestyle choices, environmental exposures, clinicopathological and genomic factors and biomarker analyses.Senesi et al. in this topic compare levels of CSF biomarkers for Creutzfeld-Jakob disease (CJD) in specimens from cases confirmed post-mortem as CJD or non-CJD, to determine the optimal cutpoints of an automated immunoassay for pre-mortem CJD diagnosis. This work illustrates the importance of definitive post-mortem brain assessment in developing clinical applications of precision neurology.Human brain banking enables cataloging and study of distinctive characteristics of individual brains, facilitating development of novel technologies for understanding the brain in health and disease. The collection of high-quality brain specimens supported by “gold-standard” postmortem diagnostic data and rich clinical and pre-clinical information that includes participant health monitoring, genomics information and neuroimaging and other biomarker studies will form the foundations upon which successful implementation of precision neurology and brain health optimization across the lifespan will ultimately depend.This topic aims to bring together researchers across these fields and raise awareness of the importance of human brain banking in precision neurology brain health optimization. It draws attention to the need for promoting and monitoring brain health—and individual factors which affect it—in partnership with living brain donors. This implicitly requires strengthening national and international policies to increase investment in brain banking so the aims of precision neurology and brain health optimization throughout the lifespan can be achieved throughout the world.YH: Conceptualization, Funding acquisition, Writing—original draft, Writing—review & editing. Q-XL: Validation, Conceptualization, Writing—review & editing. L-XC: Writing—original draft, Project administration. GW: Writing—review & editing, Conceptualization, Validation. DC: Writing—review & editing, Validation. CB: Funding acquisition, Writing—review & editing, Validation. AM: Validation, Writing—review & editing, Conceptualization.


There is no doubt about the negative impact of an unhealthy diet on Central Nervous System (CNS) development and homeostasis  “Slomp et al. used a state-of-the-art imaging approach in mice to investigate the response of GABAergic neurons (Vgat positive) to diet in a key region regulating feeding behavior, the lateral hypothalamus (LH). Their main aim was to understand whether this neuronal population might be affected by a free-choice high-fat diet (fcHFD). Their findings revealed that fcHFD reduced overall LHVgat neuronal activity, but did not disrupt the increase in activity induced by sucrose consumption. Previous studies have reported diet-induced changes in LH activity and, interestingly, the same research group observed that fcHFD altered the response of glutamatergic LH neurons to sucrose drinking  have been ascribed a leading role. Indeed, the community of more than 10 trillion microorganisms residing in our gastrointestinal tract can influence whole-body health by converting dietary components into bioactive small molecules that can enter the bloodstream, be further metabolized by the host, modulate the immune system, and reach distal organs . The 139 experimental studies and clinical trials included in their systematic review confirmed the ability of gut microbiota (and probiotics) to influence synaptic activity in hippocampal neural circuits and related behaviors. They also summarized the main molecular mechanisms known to date, including the production and modulation of neurotrophins, neurotransmitters and receptors, the regulation of intracellular molecular processes, the balance of pro-inflammatory/anti-inflammatory and pro-oxidative/anti-oxidative factors, and the preservation of histological stability of the hippocampus. However, as the authors pointed out, this field of research is still in its infancy and will require intensive future efforts to make practical advances in microbiota-based diagnosis and/or treatment of brain disorders.Freijy et al., who participated in this RT by evaluating the efficacy of probiotic supplements (a multi-species formulation of bifidobacteria and lactobacilli) on mental health. This formulation was tested in a randomized controlled trial (“The Gut Feelings”) against a high-prebiotic diet and a synbiotic (as a combination of probiotics and prebiotics) in 119 adults with moderate psychological distress (and low prebiotic intake). After 8 weeks of treatment, the authors found a reduction in total mood disturbance (the primary outcome) and improvements in anxiety, stress and sleep (secondary outcomes) only in the prebiotic group. While larger trials in both clinical and non-clinical populations are needed, their findings strongly support the importance of a healthy diet (rich in whole plant foods) as a simple and cost-effective means of promoting mental health.The importance of continuing research into the gut-brain axis has been picked up by In addition to diet, healthy physical habits are known to delay brain downfall, especially during aging. However, physical activity is not always feasible for elderly people, particularly in frail conditions such as after ischemic events. Therefore, an active research area is investigating therapeutic targets and strategies for developing exercise mimetics, particularly in CNS disorders.Ragni et al. have investigated whether dietary supplementation with a balanced essential amino acid mixture (BCAAem) influenced mitochondrial biogenesis and antioxidant response in the hippocampus of middle-aged mice compared to those evoked by treadmill exercise training. Here they have shown that BCAAem induced eNOS expression, mitochondrial biogenesis markers, and antioxidant genes in the mouse hippocampus to a degree comparable to that induced by exercise training. Furthermore, this diet supplementation promoted mitochondrial biogenesis in mouse cortical neurons in vitro and protected them from ischemic insult through mTOR and eNOS-mediated mechanism(s). This last finding is particularly interesting as the risk of ischemic stroke onset is known to be strongly increased by a metabolic derangement, and many pharmacological strategies have been attempted in this regard (Chiazza et al., in vivo models of cerebral ischemia are needed to deepen the role of BCAA-based metabolic modulators in stroke prevention or as a valuable aid in multidisciplinary post-stroke rehabilitation in humans.On this basis, As highlighted by this RT, a better understanding of how diet may influence CNS homeostasis, including through gut-brain signaling, is pivotal to provide us with effective tools to address unhealthy dietary behaviors and associated brain disorders.IB: Writing—original draft, Writing—review & editing. ST: Writing—original draft, Writing—review & editing. FC: Writing—original draft, Writing—review & editing.


Staphylococcus aureus positive left otomastoiditis. She received chemoradiation therapy along with six weeks of antibiotic therapy. A patient presenting with symptoms reflective of a sinus infection unrelieved by antibiotics with concomitant cranial nerve deficits should raise clinical concern for an intracranial pathology rather than a simple case of sinusitis.Both Gradenigo’s syndrome and Vernet syndrome are rare pathologies of the intracranial space; both involve compression of a particular anatomic location in the skull, thus affecting structures nearby or within that space. A patient presenting with one or both of these syndromes should raise concern for malignancy, head trauma, or an intracranial infection. We present a case of a 39-year-old female with three weeks of left-sided ear, face, and neck pain along with difficulty swallowing and reduced vision in the left eye. Magnetic resonance imaging of the brain revealed fullness in the left nasopharyngeal region, raising concern for malignancy or infection. Biopsy of the mass ultimately revealed Epstein-Barr virus positive nasopharyngeal carcinoma, nonkeratinizing undifferentiated type, along with culture data revealing methicillin-resistant  Multiple cranial neuropathies is a term used to describe the many foci within the skull base containing nerves that can become compressed and subsequently cause neurologic deficits ,2. Some Staphylococcus aureus. Human immunodeficiency virus testing in our patient was negative.We present a case of a 39-year-old female African American with a past medical history of hypertension and tobacco dependence presenting to the emergency department with three weeks of left-sided ear, face, and neck pain. She stated that at the time of symptom onset, she was diagnosed with sinusitis and otitis media and was prescribed amoxicillin, which did not ultimately resolve her symptoms. She was hemodynamically stable upon presentation with all vital signs within normal limits, and physical examination was remarkable for severe left-sided facial hyperesthesia, left CN VI palsy, dysphagia , voice hoarseness, and decreased strength with lifting of both shoulders upward against resistance. The remainder of her CN testing was normal, reflexes were 2+, and strength and sensation were both intact. She did not display uvular deviation from the midline. Her basic lab work including complete blood count, basic metabolic profile, and lactate were within normal limits aside from mild leukopenia of 3.7 K/uL. Computed tomography (CT) of the head was remarkable for left-sided otomastoiditis Figure , along wOnce diagnosed with nasopharyngeal carcinoma, our patient was started on a chemotherapeutic regimen of gemcitabine and cisplatin, as well as radiation therapy, and surgical intervention was not ultimately pursued. She tolerated and adhered to these treatments well and had a positive response on a follow-up positron emission tomography scan. She was maintained on a six-week antibiotic regimen following hospital discharge for otomastoiditis treatment, which initially consisted of intravenous vancomycin and ceftriaxone and was eventually converted to oral doxycycline and amoxicillin-clavulanic acid upon hospital discharge.Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis [Staphylococcus species, Streptococcus species, Haemophilus influenzae, Pseudomonas aeruginosa, and Moraxella catarrhalis; thus, initial antibiotics used to treat otitis media should cover these organisms [Gradenigo’s syndrome was first described in 1907 as a sequelae of bacterial suppurative otitis media that spreads into the intracranial space . As a serganisms .Vernet syndrome can be seen in the setting of infection, such as varicella-zoster virus or herpes simplex virus; however, malignant, vascular, or traumatic etiologies can also be seen, with the most common cause being brain metastasis ,8. Our pCommon presenting symptoms of nasopharyngeal carcinoma involve nasal and otologic symptoms , both ofGradenigo’s syndrome and Vernet syndrome presenting together should raise clinical suspicion for an underlying intracranial mass causing obstruction. It is imperative to obtain appropriate intracranial imaging in these cases to help delineate the underlying etiology. A patient presenting with typical symptoms of suppurative otitis media along with associated CN deficits should prompt further diagnostic work-up, as the patient likely has more than a simple case of otitis media or sinusitis.


The global COVID-19 pandemic resulted in many jurisdictions implementing orders restricting the movements of people to inhibit virus transmission, with recreational angling often either not permitted or access to fisheries and/or related infrastructure being prevented. Following the lifting of restrictions, initial angler surveys and licence sales suggested increased participation and effort, and altered angler demographics, but with evidence remaining limited. Here, we overcome this evidence gap by identifying temporal changes in angling interest, licence sales, and angling effort in world regions by comparing data in the ‘pre-pandemic’ (up to and including 2019); ‘acute pandemic’ (2020) and ‘COVID-acclimated’ (2021) periods. We then identified how changes can inform the development of more resilient and sustainable recreational fisheries. Interest in angling (measured here as angling-related internet search term volumes) increased substantially in all regions during 2020. Patterns in licence sales revealed marked increases in some countries during 2020 but not in others. Where licence sales increased, this was rarely sustained in 2021; where there were declines, these related to fewer tourist anglers due to movement restrictions. Data from most countries indicated a younger demographic of people who participated in angling in 2020, including in urban areas, but this was not sustained in 2021. These short-lived changes in recreational angling indicate efforts to retain younger anglers could increase overall participation levels, where efforts can target education in appropriate angling practices and create more urban angling opportunities. These efforts would then provide recreational fisheries with greater resilience to cope with future global crises, including facilitating the ability of people to access angling opportunities during periods of high societal stress.The online version contains supplementary material available at 10.1007/s11160-023-09784-5. Recreational fishing is a highly popular leisure activity, with approximately 10% of the global population participating  patterns of interest in recreational angling, (ii) angling licence sales, and (iii) angler participation and effort. We use these syntheses to consider how these patterns can inform the development of more resilient and sustainable recreational fisheries, particularly during future periods of global shocks . To facilitate comparisons of data, the following terms are used to define the time periods in the study and applied where possible: ‘pre-pandemic period’ (up to and including 2019), ‘acute pandemic period’ (2020), and ‘COVID-acclimated period’ (2021).We used a culturomics approach to identify temporal and spatial patterns in the global interest in recreational angling. Culturomics represents the study of human culture through the quantitative analysis of large bodies of digital data , a commercial smart-phone application (hereafter referred to as ‘app’) with > 14 M global users in 2022 who digitally log the details of their fishing events and catches. This generates fine-scale spatiotemporal data over large areas, so providing a de facto source of angling data to inform fisheries management  screening survey was conducted between October 2020 and April 2021. This survey was designed to determine changes in angling activities and effort during COVID-related restrictions . The survey collated general data on the proportions, socio-demographics, and heterogeneity of anglers in the German population, providing insights into changes in angling effort during restricted periods, including whether effort differed between inland and marine recreational fisheries and the effect of age, avidity, and angling skills (Section SM3)., before they returned to pre-pandemic levels in the COVID-acclimated period of 2021 . Weekly licence sales in the same period showed an opposite effect, with sales crashing following the 2020 lockdown , presumably because these mandatory licences are mainly purchased by non-Danish tourists who were unable to travel and/or legally enter Denmark. In England, where a licence is only needed to fish in inland waters with rod and line, COVID-19 restrictions in 2020 resulted in no angling in April, partial restrictions from May to July and September to December, and no restrictions in August. There were also no restrictions in 2021. Licence sales across all types increased by 18% in 2020 compared to 2019, especially from May to July, but returned to 2019 levels in 2021 . Licence sale data from Germany showed inconsistent patterns among federal states , with sales varying little in Bavaria with no COVID-19 alteration in 2020 (Section SR1), whereas memberships of the state angler association of Brandenburg increased by approximately 7% in 2020, although memberships were already increasing prior to the COVID period (Section SR1). Coastal fishing licences in Mecklenburg-Western Pomerania, which strongly depend on domestic tourists , with sale data categorised by angler origin (Table S1). The main pattern detected in these data was a pronounced reduction in sales to non-resident  anglers between 2019 and 2020 (-89%), whereas licence sales to Ontario anglers increased by 10% in the same period, suggesting increased activity by anglers who had no option but to fish locally (Table S1). In Brazil, there is a requirement to purchase an annual national fishing licence for both marine and freshwater angling, with state licences also often being required  in April and May 2020. The median ratio of sales of recreational fishing permits relative to April and May 2019 was only 78%, which was lower than the median of 93% for the 196 fisheries cooperatives in other regions of the country. This result indicates reduced sales, likely because restrictions of the movement of people prevented most, if not all, angling activities. However, the 2020 Japanese domestic shipment value of recreational fishing equipment, in particular marine shore fishing equipment, was the highest recorded since 2010. A small number of the inland fisheries cooperatives either postponed their opening dates of the ayu All metrics derived from the smartphone app ‘Fishbrain’ in Europe, North America, and Oceania were trending upward from 2015 to 2019 , ~ 60% had fished during the acute pandemic period, with most inland anglers fishing as frequently as in the pre-pandemic period. Only 21% of the inland anglers fished more than usual. Although inland anglers generally continued their fishing activities, > 50% of those fishing in marine waters of the Baltic and North Sea reduced or stopped fishing during the acute pandemic period Fig. , most liComparisons of Danish angler traits  in periods of pre-pandemic , acute pandemic (2020) and COVID-acclimated (2021) revealed that angling participants in 2020 were younger, less experienced, and more urban-based than participants in 2018 and 2019, but with anglers in spring 2021 being more similar to pre-pandemic participants . Thus, the 2020 shifts in angler characteristics represented a short-term response to the COVID-19 restrictions.There were some strong pandemic-related changes in the behaviour of individual anglers and overall patterns of interest, effort, and engagement, with trends including a peak in online interest in recreational angling in 2020, shifts in angler behaviours and demographics, and some changes in licence sales. While these trends varied by region, they generally reflected country-specific COVID-19 restrictions and long-term patterns of sales and activity . There is greater uncertainty as to whether local effort changed , but more evidence indicated that changes were highly transitory and quickly reversed by 2021.There were some context dependencies in these results and evaluations at country and regional levels. In entirety, however, we argue that they provide a series of considerations that can contribute to the development of more resilient, responsible, and sustainable recreational fisheries  should help retention, while also serving as a vehicle for instilling responsible fishing practices and knowledge transfer related to regulations and other management tools. Indeed, anglers who were associated with angling clubs in Germany remained most active during periods of movement restrictions  had negative impacts on the recreational fishing industry and its members, although some sectors might have boomed (e.g. online stores). As jurisdictions transition to COVID-acclimation periods, consideration is needed to ensure that relevant sectors can remain vibrant and support livelihoods while also ensuring angling participants can continue to access the services that they require. Achieving this might need policy adaptation through promotion of a “whole of government” approach, and the development of recreational fisheries-directed facilities and services . We have demonstrated here that some considerable changes in angling interest, behaviour and effort also occurred in this period. While acknowledging that the licence and effort data were imperfect, we argue these data emphasise the importance of overcoming these imperfections through improved data collection in recreational fisheries more generally. Indeed, the acknowledgement that there remain substantial gaps in our understanding of how recreational anglers respond to changes in social circumstances more generally is a major step forward in understanding how to overcome these issues. The collated information did demonstrate that, whilst there was some high spatial variability in some results, there were some distinct patterns in both licence sales and effort, including the loss of tourist anglers. Furthermore, people also had to fish more locally, with these people often being younger than most anglers who fished prior to the pandemic. In some regions, however, we have also seen a rapid transition back to pre-pandemic conditions, suggesting that the changes were not sustained. Thus, despite the apparent attractiveness of recreational angling during periods of high individual and societal stress, the retention of new anglers remains elusive. Managers and policymakers can use the data and considerations here to ensure that their fisheries remain accessible for the benefit of anglers of all ages and abilities, while ensuring that these fisheries can be used to help recruit and retain new anglers—irrespective of the overriding economic and public health conditions.Supplementary file1 (DOCX 1126 kb)Below is the link to the electronic supplementary material.


SlSPCH cis-regulatory sequences in tomato, that we can identify variants with altered stomatal development responses to light and temperature cues. Analysis of tomato leaf development across different conditions, aided by newly-created tools for live-cell imaging and translational reporters of SlSPCH and its paralogues SlMUTE and SlFAMA, revealed the series of cellular events that lead to the environmental change-driven responses in leaf form. Plants bearing the novel SlSPCH variants generated in this study are powerful resources for fundamental and applied studies of tomato resilience in response to climate change.Flexible developmental programs enable plants to customize their organ size and cellular composition. In leaves of eudicots, the stomatal lineage produces two essential cell types, stomata and pavement cells, but the total numbers and ratio of these cell types can vary. Central to this flexibility is the stomatal lineage initiating transcription factor, SPEECHLESS (SPCH). Here we show, by multiplex CRISPR/Cas9 editing of  Stomata opening and closing responses occur within minutes of a change in light, water availability, carbon dioxide concentration ( will increase, and severe weather events  will become more prevalent (Nearly all future climate predictions suggest that temperatures and atmospheric [COrevalent , 51. StoSupplement 1Supplement 2


Chronic ocular pain is a common, debilitating chronic pain condition with significant morbidity and negative impact in patients’ quality of life. Several, diverse types of insults to the ocular surface can lead to acute, and under certain conditions to chronic ocular pain, and these include toxic irritants. Exposure of ocular surface to toxic irritants, in addition to direct tissue injury, carries the capacity to generated intense immune and neuronal responses with hyper-excitability, sensitization and chronic pain. Because, chronic ocular pain subsequent to toxic exposures is relatively unrecognized clinical entity, this brief review highlights pertinent concepts of its epidemiology, pathogenesis/pathophysiology, clinical progression, with recommendations for its clinical management that clinicians may find helpful. Suppression of pain signaling, generating neuronal sensitization, and prevention of chronicity of neuropathic pain is particularly emphasized in this respect. Chronic ocular pain (COP) is a common and debilitating form of chronic pain, perceived as originating from the ocular surface, and frequently extending to adjacent facial structures; including the eyelids, supra/infra-orbital face, and/or the temporal region ; 2022.COP manifests as spontaneous pain, frequently accompanied by intensely abnormal sensations , as well as orofacial pain, TMJ pain, and headaches. It is associated with significant psycho-social dysfunction and can contribute to an extremely poor quality of life .The etiology, pathogenesis, and pathophysiology of chronic ocular pain is variable and includes traumatic, post-surgical, post-LASIK , chemicaChronic ocular pain can be persistent and debilitating. It has been suggested that easing the burden of COP requires further exploration of its neurophysiology, diagnostic modalities, preventative and treatment strategies . This reCOP remains extremely difficult to treat partly because of its diverse etiology and pathophysiology, because of insufficient knowledge of its underlying mechanisms, and partly because of the lack of specific treatments. Currently available treatment options include various, mostly systemic, analgesic medications, the use of which is limited by significant untoward side-effects .Better understanding of the possible causes of COP, its cause-specific pathogenesis, and treatment options may have a positive impact towards its prevention and therapy. Chronic ocular pain generally remains an underappreciated, underdiagnosed and undertreated disease entity, and many ophthalmologists as well as non-ophthalmologist physicians  are at a loss when they treat patients suffering from eye pain, including chronic pain subsequent to toxic chemical insults to the eye. To their assistance, this review aims to highlight pertinent concepts to ocular pain as a result of toxic chemical irritants to the eye surface. These toxic injuries are common and may have a huge impact on the quality of life of patients, not only from the perspective of loss of vision, but from the perspective of chronic, debilitating pain as well. This brief review will highlight basic concepts pertinent to this condition that should be brought to the attention of non-ophthalmology practitioners.Ocular chemical injuries are more likely to occur in the workplace than at home. Toxic chemical injuries account for the second-most common ocular workplace injuries (10%–25%), behind foreign body ocular injuries (35%–50%). Most injuries are reported in the industrial service injury. Men are at least 2 times more likely to suffer a chemical ocular injury than women. Chemical injuries occurring at home are more common in the pediatric population, particularly involving household cleaning agents, medications, and agricultural chemicals . In all The incidence of developing chronic ocular pain from a toxic chemical ocular injury is largely unknown and likely underreported. There are, however, several case reports of patients suffering from chronic ocular pain after chemical injuries from a variety of agents . In a deThe surface of the eye, particularly the cornea, is the most densely innervated tissue in the body with a nerve density up to 600 times that of the skin, and up to 40 times that of the tooth pulp . PeripheBecause the majority of sensory afferent neurons in the cornea are nociceptors , the priThe central axons of the trigeminal afferents innervating the cornea project onto two distinct regions of the trigeminal subnucleus caudalis (Vc), specifically to the rostral caudalis/interpolaris transition region (Vi/Vc) and the more caudally located Vc junction in the upper cervical spinal cord (Vc/C1) . These aVarious animal models of pain after toxic exposure to the eye have been proposed as means to study those mechanisms. These models employ instillations of toxic chemical to the cornea of animals, such as alkali, or other irritants, and subsequent evaluation of pathological, pathophysiological and neurobehavioral parameters. These (mostly rat and cat) animal models utilize either objective behavioral methods of measuring presence of ocular pain (ie: increase in blinking) or measure changes in neuron firing via surgical insertion of electrodes at various sites along pain pathways . These sin vivo confocal microscopy, although these tests are largely limited to evaluating the ocular surface  diagnostic tools to detect the insulting neural etiologies in patients suffering from COP , and thi surface . While fChemical injuries to the surface of the eye cause direct corneal and eye surface injury, including ulcers, as well as inflammation and subsequent events leading to pain, that under some conditions may become chronic . Yet, chChemical toxicity by silver nitrate  has reveThis inflammatory response subsequent to chemical toxicity is accompanied by increased sensitivity to stimuli  by which application of stimuli produces exaggerated responses. This hyperalgesic response is analogous to the acute inflammatory response with hypersensitivity observed in cutaneous tissues after similar noxious toxicity, including edema, neutrophil aggregation and hyperalgesia. In contrast to cutaneous tissue, however, the cornea is not vascularized, therefore corneal inflammation subsequent to chemical toxicity follows a more delayed and prolonged time course and immune cell (mainly neutrophil) infiltration . The samThis has been supported by another animal model of corneal toxicity, induced by repeated topical installations of 0.2% benzalkonium chloride (BAC) onto the left eye of mice . This moOther models that include chemical toxicity by 0.75 N NaOH alkali solution to the cornea have revealed the development of corneal nerve damage with an acute profound loss of corneal nerve density, which is followed by a delayed but aberrant reinnervation. Corneal nerve damage was accompanied by ocular hyperalgesia in that model. Furthermore, several abnormalities have been observed in the reinnervating nerves such as neuroma formation, increased tortuosity, beading, and abnormal branching, indicating the presence of mechanisms that contribute to neuropathic pain, in addition to nociception and inflammation . TherefoSo, it seems very likely that the initial noxious insult from toxic exposure to the cornea may initiate activation of the corneal nociceptors, their sensitization, and generation of afferent nociceptive signals, and synaptic excitatory input to central nociceptive pathways that mediate the sensation of pain and the establishment of central sensitization. While varying types of chemicals may induce differentiating histopathological injuries and penetrate a variety of ocular layers, it is likely that a common pain pathway is shared among these injuries. Sensory nerve fibers  originating from the ophthalmic division of the trigeminal nerve are activated directly via chemical activation of free nerve endings, polymodal receptors, via ectopic transmission, or damage to nerve axons inducing pathological pain signal transmission. These signals may originate at any of the terminal ocular branches of the trigeminal nerve, transmit to the trigeminal brainstem complex, then project centrally to the posterior thalamus and a variety of cortical targets including the insular cortex, amygdala, somatosensory and prefrontal cortex . PeripheIn order to guide treatment efforts, grading the extent of the ocular injury is done via either the Roper-Hall classification and/or the Dua et al. classification systems. The Roper-Hall classification system is based on the extent of corneal injury and limbal conjunctival ischemia. It does not consider direct conjunctival injury. The Dua et al. classification system factors in conjunctival injury (percentage of injury) and limbal injury (graded by surface-area “clock hours”). The Dua et al. classification system does not, however, factor in corneal injury. A significant drawback to both classification systems is that neither system takes into consideration the depth of chemical injury, which is of particular significance when considering the pathological etiology for patients’ presentations of COP . FurtherNumerous toxic chemicals in existence can cause ocular damage upon direct exposure to the ocular surface. However, similar pathological reactions are seen within certain groups of chemicals. There are largely 3 different groups of toxic chemicals that induce specific reactions: acids, bases, and “other” chemicals. It is unknown currently whether a certain group of chemicals induces COP with a higher incidence than another group of toxic chemicals.2, a chemical compound commonly used in plastering or cementing. The calcium component produces a soap upon saponification within the epithelium, which hinders further penetration into the eye. Ammonia (NH3) is a compound used mostly in manufacturing, in fertilizer, and in the chemical industry. It has the fastest rate of penetration through the ocular surface. Another compound with a fast penetration rate is lye (NaOH), which is a common chemical component in drain cleaning products. Other alkali chemicals commonly encountered include potash (KOH), used in the chemical industry, or Mg(OH)2, which is found in some fireworks  than acidic chemicals. Alkali injuries are particularly significant if the pH of the chemical irritant is > 11.5 . Alkali ireworks .2SO4). Sulfuric acid is primarily found in car batteries, fertilizer, or used in the metal industry. Other acidic chemicals that commonly cause ocular injuries include HCl  or nitric acid  , can penetrate deeper into the anterior chamber of the eye. HF is used for rust removal, brick cleaning, pottery glazing, as a lab reagent, and is sometimes used in the semiconductor industry. Yet, the most common ocular injury from acidic chemicals is due to sulfuric acid (Hcturing) .2O2 is usually no more than just an irritant to the corneal surface. Similarly, alcohol solutions generally cause limited irritation. Formaldehyde, which is used as a preservative, causes mild irritation initially, but it can potentially penetrate the anterior chamber of the eye if it is not promptly washed out  or hydrocarbon solvents (used as cleaning/dissolving substances or paint thinners). These chemicals generally cause superficial pain upon irritation of the cornea, but they do not generally further penetrate the eye. At low concentrations typically encountered, irritant lacrimators (such as pepper-spray) similarly cause corneal nerve stimulation without further structural injury. Cyanoacrylate adhesives (found in a variety of glue preparations) can cause corneal damage from abrasions due to rapid adherence of the eyelids to the cornea. At household strength, Hshed out .There are no known definitive ophthalmologic interventions that prevent the development of chronic neuropathic ocular pain after injury from chemical exposure. It is these authors’ belief that the best way to prevent chronic neuropathic ocular pain after injury from chemical exposure is to promptly eliminate the toxic irritant from the ocular surface, to address ocular surface inflammation, and to offer acute pain control. It is important to prevent further ocular pathology, to promote ocular healing, and to manage patient co-morbidities.® (an acid (H+) and fluoride (F-) ion absorbent) may yield superior irrigating results. Oil or EDTA may be a preferred irrigating solution for quicklime  ocular burns  may prevent worsening ocular edema . Amphotear burns . IrrigatWhile ocular irrigation is imperative to initial treatment efforts of patients with ocular chemical injuries, there must be an emphasis towards ensuring total chemical decontamination of both patients and caretakers. The Occupational Health and Safety Administration (OSHA) outlines an evidence-based decontamination plan that can protect patients and caretakers from further injury after exposure to chemical agents . PreventAfter irrigation, an ophthalmologist or emergency medicine provider should instill anesthetic eye-drops and remove any obvious particulate matter on the ocular surface. Adequate acute pain control is imperative for a thorough ocular assessment and continued therapeutic efforts. While not studied directly in the setting of COP, there is evidence to suggest that chronic post-traumatic pain may be avoided by preventing significant central sensitization to pain with adequate pain control in the acute phases of tissue injury . Acute pAt this juncture the ophthalmologist’s therapies will be targeted to reduce further ocular inflammation, prevent further corneal melting, and management of potential increases in intra-ocular pressure (IOP). Steroid eye drops (dexamethasone or prednisolone) can be utilized to reduce inflammation and minimize proteolytic enzyme release within the cornea. It is of interesting note that topical NSAIDs are discouraged to manage inflammation, as they may contribute to further corneal melting. Sodium citrate eye drops, and oral tetracycline have also been shown to suppress the release of damaging proteolytic enzymes. IOP is managed with eye drops or laser therapy . In certain instances, high IOP requires surgical management  .ex-vivo cultivated limbal epithelial transplantation, or a simple limbal epithelial transplantation). Finally, a variety of corneal transplants (keratoplasty or keratoprosthesis) may be considered  therapy, or amniotic membrane transplantation. If there is a deficiency in limbal stem cells from extensive chemical injury, a limbal stem-cell transplantation can be considered to promote re-epithelialization   .The management of COP is currently largely underdeveloped. This also applies to COP after toxic chemical injuries to the eye. Therapies are largely concentrated at treating neuropathic-type pain, not-specific to corneal nerves. Specific evidence-based therapies are lacking in current literature. Nevertheless, a multi-step approach at managing the patient’s pain is likely most beneficial. Therapeutic strategies aim to promote ocular surface healing, decrease inflammation, induce appropriate nerve regeneration, manage pain, and manage patient co-morbidities. An interdisciplinary approach is beneficial, as an ophthalmologist may manage ocular healing, a psychiatrist may manage concurrent psychological pathologies that frequent accompanies neuropathic eye pain and may contribute to overall illness and worsened pain control, a pain specialist may manage analgesic efforts, and a general practitioner may manage any other co-morbidities that can contribute to poor healing . Local tAlternative therapies may be beneficial, particularly if used in conjunction to systemic pharmacotherapy. These therapies may include acupuncture, transcranial magnetic stimulation, or percutaneous electrical nerve stimulation, such as TENS applied peri-orbitally, or scrambler therapy. Nerve regenerative therapies are also described, such as autologous serum eye drops at a concentration of 20%–100%. While other types of regenerative therapies such as platelet rich plasma, nerve growth factor, and umbilical cord serum eye drops may be beneficial, they are not easily accessible at this time in the United States . Other iCOP is a debilitating chronic pain condition that is often underdiagnosed and undertreated. It is a common occurrence after significant ocular damage from toxic chemical exposure. Patients with COP following chemical injuries may present to a chronic pain provider, and it is imperative to understand the basic epidemiology, pathophysiology, diagnostic modalities, and treatment options for these patients. Further research is needed to better elucidate the formation of chronic ocular pain after toxic chemical exposure. Additionally, further therapeutic options should be researched to better manage patients with chronic ocular pain.