The COVID-19 pandemic caused by SARS-CoV-2 has highlighted consistent inequities in the risk of infection, severity of disease, or mortality across racial and ethnic minority populations in the United States and beyond. Although novel, SARS-CoV-2 shares commonalities in transmission dynamics with other viral respiratory pathogens where similar disparities in morbidity and mortality have been documented. However, to date, there has not been a systematic review of disparities in viral respiratory pathogens. In response, this review aims to synthesize data on racial and ethnic disparities in morbidity and mortality due to viral acute respiratory infections (ARI) other than SARS-CoV-2. In particular, this review will focus on understanding structural health and social factors outside of race and ethnicity driving these disparities in the United States.We will conduct a systematic review of studies published between January 1, 2002 and September 30, 2020 that capture data on racial and ethnic disparities associated with increased incidence, disease severity, risk of hospitalization and/or death in viral ARI in the United States. Data characterizing individual-, community-, and structural-level factors associated with these disparities will be abstracted to better understand the underlying structural inequities contributing to racial disparities in ARI. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses  guidelinFindings from this systematic review will shed light on patterns of racial and ethnic disparities in viral ARI in the United States. Leveraging these data can support predictive studies of the differential impacts of COVID-19 across the United States as well as adaptive intervention strategies mitigating structural inequities, including structural racism, driving both incidence and disparities in marginalized communities. Moreover, data emerging from this review may reignite pandemic preparedness focused on vulnerable communities given structural inequities, facilitating improved future pandemic responses to novel or endemic viral respiratory pathogens in the United States.PROSPERO CRD42020219771 Emerging evidence has highlighted the stark racial and ethnic disparities in the risk of infection and death caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. In the United States, African American, Latinx, and indigenous populations comprise a disproportionate number of COVID-19-related deaths . NotablyDespite the growing interest to explore literature concerning racial disparities and social determinants of ARI, there are no systematic reviews comprehensively characterizing research focused on racial and ethnic disparities from former infectious disease outbreaks of viral respiratory pathogens . Aside fConsidering the ever-growing focus on the contribution of racial inequities to multiple facets of health, and the present burden of COVID-19-related deaths on African-American, Latinx, and indigenous communities in the current pandemic, it is imperative to understand factors, including structural racism, that have contributed to these disparities in earlier outbreaks. Such knowledge would inform development of a pandemic preparedness response that ensures protection of the most vulnerable.Framing pandemic preparedness through a social justice lens is not a novel concept and has been previously emphasized as integral to mounting an effective response strategy –13. NeveThis systematic review will assess data published between January 1, 2002 and September 30, 2020 that characterizes the racial and ethnic disparities associated with increased incidence, disease severity, risk of hospitalization, or death in viral acute respiratory infections, other than SARS-CoV-2, in the United States. We will additionally summarize data in this same time period that describes the individual-, community-, and structural-level factors correlated with race/ethnicity  that are associated with increased morbidity and mortality in acute respiratory infections.To complete a systematic review of available data capturing racial and ethnic disparities in the incidence, morbidity, and mortality of viral acute respiratory infections from 2002 to 2020 in the United States.To determine which racial/ethnic populations are disproportionately affected and evaluate underlying drivers of these disparities including structural racismARI incidenceDisease severity/complication due to ARIHospitalization due to ARIDeath attributed to ARISecondary outcomes of this review will assess uptake of preventive interventions shown to be effective for mitigating the spread of viral respiratory pathogens. These include vaccine coverage and uptake, handwashing, social distancing, and wearing masks .This protocol is registered under the PROSPERO database (CRD42020219771) and designed in accordance with standardized guidelines specified in the Preferred Reporting Items for Systematic Reviews and Meta-analyses  see Add 16). Fi. Fi16). Inclusion & exclusion criteriaTo be included in the review, an article must meet the following criteria:Studies will capture data on persons of any age who are at risk for, or infected with, a respiratory viral pathogen , middle east respiratory syndrome (MERS), severe acute respiratory syndrome coronavirus 1 (SARS), parainfluenza virus, measles virus, rubella virus, rhinovirus, and/or adenovirus).Studies will measure the following as an exposure: Non-white race/ethnicity, such as Black/African American, Asian, American Indian/Alaska Native, Native Hawaiian/other Pacific Islander, non-white Hispanic or Latinx, as defined by the United States Census Bureau .Studies will measure one or more of the primary or secondary outcomes listed above.Studies were publications in peer-reviewed journals or an abstract at a conference with peer-reviewed blinded abstract selection process.At a minimum, studies captured and reported information on racial/ethnic disparities in ARI and listed details regarding data sampling techniques.Articles published since January 1, 2002 with data collection started no later than January 1, 2000.All studies were conducted in English and based in the United StatesArticles will be excluded based on the following criteria:Study only addresses disparities with the novel SARS-CoV-2 that causes COVID-19Study was conducted outside of the United StatesStudy conducted among non-human, animal subjectsSample size is less than 100 personsStudy does not mention race/ethnicity in the abstractStudy is based on modelling dataStudy designsWe will include primary studies of any design that describe racial/ethnic disparities associated with respiratory infections due to influenza virus, RSV, MERS, SARS, parainfluenza virus, measles virus, rubella virus, rhinovirus, and/or adenovirus. Studies will be included when non-white race/ethnicity is compared to the following: no comparison; white race/ethnicity; other non-white race/ethnicityInformation sources and search strategiesIn partnership with an information specialist at Johns Hopkins University, we will search the following electronic databases: the National Library of Medicine’s MEDLINE database using the PubMED interface, EBSCO Host- CINAHL Plus, PsycInfo, EMBASE, and Cochrane Library. Search criteria and terms were created based on validated peer-reviewed systematic reviews and articles regarding racial disparities and acute respiratory infections . We willWe piloted multiple search strategies to optimize an approach that is highly sensitive yet prioritizes identifying relevant articles. The search strategies are comprised of a combination of controlled MeSH terms and other search terms that cover two independent concepts: acute respiratory infections and racial/ethnic disparities see . Search Study selection & quality assessmentThe literature review consists of an iterative title review, abstract review, and full text review for articles that meet the criteria . Two revStrategy for data extractionData will be extracted for each full article reviewed and entered into a pre-piloted data collection form based on COVIDENCE—a commercially available web-based tool for conducting and managing systematic reviews. Reviewers will be trained to abstract the relevant data from the articles using the data abstraction tool.The following fields will be abstracted from all included studies:Source referenceSource type  and publication yearPopulation Geographic setting (within the United States)Sample sizeNature of study Study design Individual-, community-level, or structural-level factors discussedType of individual-, community-, or structural-level factor discussed Measures of effect for all primary or secondary outcomes of interest, including proportions, relative risks, odds ratios, or hazard ratios if time series data availableSummary of author interpretations/conclusionsSynthesis and feasibility for meta-analysisData will be analyzed according to study outcomes and race/ethnicity exposures. For qualitative research, we will present descriptive summaries, and if race/ethnicity exposures are similarly measured, we will assess consistency of thematic results. For quantitative studies reporting the same outcome, among populations deemed suficiently similar, we will conduct meta-analysis using random effects meta-analytic models. We will evaluate heterogeneity within selected studies by examining forest plots and conducting Cochrane’s Q and I2 statistical tests. We will assess the quality of the body of evidence contributing to the pooled effect estimate for each outcome using criteria recommended by the GRADE Working Group: GRADE evidence certainty for individual outcomes –25. FunnThe aim of this review is to investigate disparities in morbidity and mortality in acute respiratory viral infections other than SARS-CoV-2. Some practical challenges are expected in the identification of existing evidence. First, the medical library indexing of articles may influence the results obtained in this review. It is common practice to report outcomes by race, however, if differential outcomes are not a primary objective of the study, the article may not be indexed in the medical library accordingly. Therefore, these studies may not be represented in this review.Second, racial and ethnic disparities are documented to be associated with interrelated socioeconomic factors representing macrolevel inequalities such as income, neighborhood, stigma and discrimination, and barriers or access to healthcare . Given tThe findings from this systematic review will provide context and insight to understand patterns of disparity in viral acute respiratory infections in the United States. Furthermore, this review may support a robust comprehension of the manifestations of structural and social inequities affecting racial and ethnic minorities and their influence on ARI outcomes. Leveraging this information could influence development and implementation of studies on the differential impact of COVID-19 across the United States. Moreover, this information could be used to inform the development of strategies to alleviate the structural inequities driving racial and ethnic disparities prevalent in ARI. Finally, the newly elected President- and Vice President-elect recently proposed the establishment of a COVID-19 Racial and Ethnic Disparities Task Force as an integral component of their plans to address the ongoing COVID-19 pandemic . We hopeSupplementSupplement


The Head Start program, including Head Start for children aged 3–5 years and Early Head Start for infants, toddlers, and pregnant women, promotes early learning and healthy development among children aged 0–5 years whose families meet the annually adjusted Federal Poverty GuidelinesIn collaboration with ACF, CDC conducted a mixed-methods study during September–October 2020 in Head Start programs in eight states . Head Start programs, each with five to 17 centers and 500–2,500 children, were selected by the Office of Head Start. The four-phase study design included reviews of standard operating procedures (SOPs) for COVID-19 mitigation, deployment of an online survey for program directors to document mitigation strategies implemented and COVID-19 cases reported, in-depth interviews with staff members from five programs overall, and observation of mitigation strategy implementation during a virtual visit to one Head Start site. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.All program sites closed for periods ranging from 2 weeks to 2 months after state-initiated mandates in April and May and upon reopening offered a hybridSeven of eight Head Start programs, representing 55 centers, responded to the survey. All reported implementing SOPs and adjusting them depending on guidance from the local public health authorities or education department, local level of transmission and related factors described below. Multiple strategies were implemented simultaneously, including training teachers and encouraging caretakers to adhere to SOPs and mitigation strategies; instituting flexible medical leave policies for staff members; providing and requiring use of masks for all staff members and children; and supervising handwashing and hand-sanitizing for children . VariatiBOXEveryday prevention actionsReinforcement of hand hygiene behavior and respiratory etiquetteSupervised handwashing and hand-sanitizing for childrenIntensified cleaning and disinfection efforts Required use of masks for staff members, visitors, and children aged >2 yearsSocial distancing to the extent possibleDaily health screening procedures on arrival for children and staff membersDrop-off and pick-up proceduresMonitoring for absenteeismAbility to monitor and restock suppliesSteps to increase ventilation including installation of ion air purifiersSteps to decrease occupancy in areas without increased ventilationUse of outdoor space as much as possibleCohorting by classroom to minimize exposure between groupsActions when someone is illCOVID-19 point of contact identifiedStaff members trained in COVID-19 safety protocolsRequiring ill children and staff members to stay at homeVigilance for symptomsDaily screening of staff members and children for signs and symptoms before facility entryStandard operating procedures for when a child or staff member experiences symptomsIdentification of isolation roomPlan to notify local health official of COVID-19 casesPlan to distribute instructions for primary care referral, testing, or bothPlan to distribute instructions or guidance for home isolationPlan to require close contacts to wait 14 days before returningFlexible COVID-19 medical leave policies for staff membersCommunications and supportTraining and ongoing reinforcing of standard operating procedures and mitigation measures with caregivers, teachers, and other staff membersVigilance and training for the identification of COVID-19 related symptomsMasks and other personal protective equipment  provided to teachers and other staff membersIncentives to adhere to mitigation strategiesFlexible medical leave policies for staff members with emphasis on persons at higher risk for severe illness and those with caregiving responsibilitiesFlexible work hours and staggered shiftsTelework options for staff members at higher risk for severe illnessAbbreviation: COVID-19 = coronavirus disease 2019.* Alaska, Georgia, Idaho, Maine, Missouri, Texas, Washington, and Wisconsin.All programs reported having plans in place for managing children and staff members experiencing COVID-19 symptoms. Three programs identified nine cases among children in three centers (range = one to four cases per center) during May and June. Administrators followed SOPs for notification, isolation, facility closure, and cleaning and disinfection. All three centers were closed for in-person operation for 14 days after identification of a case but offered virtual options to continue providing services. Respondents from all seven programs reported that centers had a designated isolation area. One program did not report whether a designated isolation area existed; however, this program reported ability to isolate a suspected case. All but one program had a protocol for working with the local health department if a positive case was identified; all indicated that the local health department would be contacted if a case was identified. All programs had established procedures for notifying parents or caregivers of close contacts.Interviews were conducted in September and October with program directors identified by the Office of Head Start in five states . A common theme identified was the flexibility offered for staffing and operations, including flexible medical leave, enhanced benefits during the pandemic , and remote working options. Staff members who were at increased risk for severe illnessA second theme identified was ongoing communications among program administrators, parents and caregivers, and teachers and other staff members to ensure understanding of SOPs. Communications included updates on program websites, development of instructional videos, written information, virtual meetings, media coverage, social media postings, and posted signage at facilities.Factors facilitating successful implementation of mitigation strategies included extensive communication with consistent messaging to staff members and parents; ongoing training and support to staff members; continuous engagement of community partners and parents; and collaboration with program nurses, local health departments, hospital systems, and community organizations . Challenges included maintaining recommended social distancing, ventilation, weather concerns during the fall and heading into winter, parental mental health concerns , questions concerning effects of staff members wearing masks on infant and toddler psychosocial development, maintaining guidance vigilance, and concern that programs were being overly cautious.A virtual visit to a Head Start site in Texas found that staff members and children observed social distancing. In rooms with children aged <2 years, mask use was only observed among staff members, per CDC guidelines. Physical dividers were observed, including an innovative playground divider purchased with CARES Act funding that allowed for more outdoor play time for children. Cleaning and disinfecting protocols were described, along with guidance for stocking and monitoring the supply room to ensure adequate supplies. Plans for responding to positive SARS-CoV-2 tests were reviewed, and all included a rapid notification system for all enrolled families. To continue enrollment for the fall, a contactless application system using quick-response codes on community flyers had been implemented.Children can acquire and transmit SARS-CoV-2 in school and child care settings  are many. Understanding child care programs’ capabilities for implementing COVID-19 mitigation strategies provides practical information that public health officials, child care setting administrators, and evaluators can use to implement and adjust strategies to reduce SARS-CoV-2 transmission. Child care settings should implement concurrent preventive measures and adjust these strategies based on community transmission data (The benefits of in-person child care programs are myriad; however, SARS-CoV-2 transmission has been documented in child care facilities.Head Start and Early Head Start programs successfully implemented CDC-recommended guidance and other ancillary measures for child care programs that remained open, allowing them to continue offering in-person learning. These approaches were documented to guide implementation of mitigation strategies in child care settings.Implementing and monitoring adherence to recommended mitigation strategies can reduce risk for SARS-CoV-2 transmission in child care settings. These approaches could be applied to other early care and education settings that remain open for in-person learning and potentially reduce the spread of coronavirus disease 2019.


Nasalis larvatus), Sarawak surili (Presbytis chrysomelas), Bornean orangutans (Pongo pygmaeus) and tufted ground squirrel (Rheithrosciurus macrotis). Under its slated development trajectory, the local and trans-national forest connectivity between Malaysian Borneo and Indonesian Borneo would also be substantially diminished. Nearly ~161 km of the Pan-Borneo Highway in Sarawak will traverse forested landscapes and ~55 km will traverse carbon-rich peatlands. The 13 hydroelectric dam projects will collectively impact ~1.7 million ha of forest in Sarawak. The consequences of planned highway and hydroelectric dams construction will increase the carbon footprint of development in the region. Moreover, many new road segments and hydroelectric dams would be built on steep slopes in high-rainfall zones and forested areas, increasing both construction and ongoing maintenance costs. The projects would also alter livelihood activities of downstream communities, risking their long-term sustainability. Overall, our findings identify major economic, social and environmental risks for several planned road segments in Sarawak—such as those between Telok Melano and Kuching; Sibu and Bintulu; and in the Lambir, Limbang and Lawas regions—and dam projects—such as Tutoh, Limbang, Lawas, Baram, Linau, Ulu Air and Baleh dams. Such projects need to be reviewed to ensure they reflect Borneo’s unique environmental and forest ecosystem values, the aspirations of local communities and long-term sustainability of the projects rather than being assessed solely on their short-term economic returns.The forests of Borneo—the third largest island on the planet—sustain some of the highest biodiversity and carbon storage in the world. The forests also provide vital ecosystem services and livelihood support for millions of people in the region, including many indigenous communities. The Pan-Borneo Highway and several hydroelectric dams are planned or already under construction in Sarawak, a Malaysian state comprising part of the Borneo. This development seeks to enhance economic growth and regional connectivity, support community access to services, and promote industrial development. However, the implications of the development of highway and dams for forest integrity, biodiversity and ecosystem services remained largely unreported. We assessed these development projects using fine-scale biophysical and environmental data and found several environmental and socioeconomic risks associated with the projects. The highway and hydroelectric dam projects will impact 32 protected areas including numerous key habitats of threatened species such as the proboscis monkey ( The forest of Borneo is one of the last remaining tropical forest strongholds on the planet. The island harbours 37 million hectares (Mha) of biodiversity-rich tropical forests  as well Borneo’s forest  is disapSarawak continues to implement several infrastructure expansion projects, mainly roads and hydroelectric dams, to enhance economic growth . The PanThe Sarawak dams are being constructed to supply electricity for planned industrial developments and to export electricity to nearby Indonesian Borneo and Sabah, Malaysia . The PanThe roads and dams in forested landscapes may, however, also generate numerous negative environmental, economic and social impacts –20. ThesPongo pygmaeus), pygmy elephants (Elephas maximus borneensis), bearded pigs (Sus barbatus) and sun bears —which require large home range to maintain viable populations [Ensuring habitat connectivity and minimal disturbance to forest areas in Sarawak is important for Borneo as a whole. Borneo hosts several iconic species—such as Bornean orangutans  using Graphical User Interface for the Description of Image Objects and their Shapes (Guidos Toolbox 2.6 version 4) , 37, folIn MSPA, we defined forest cover using the latest forest cover data for Borneo , which aBeyond landscape connectivity, we also assessed the likelihoods that the highway and hydroelectric dams may impact current forest cover in Sarawak. For this purpose, we classified forest into primary and selectively-logged forest and spatially overlaid the highway routes and hydroelectric dams’ location. Then we spatially assessed primary and selectively-logged forest areas within a 1-km buffer of the highway and a 25-km radius of the dams in a GIS interface. For this analysis, we used forest cover data from Gaveau, et al.  as descrPresbytis chrysomelas) and proboscis monkey  were obtained from IUCN [2 resolution [We assessed the highway and hydroelectric dams with respect to protected areas, peatland and slopes. As such, we spatially overlaid the highway routes and hydroelectric dams’ locations on the above landscape features across Sarawak in a GIS interface. The protected area data were extracted from Global Forest Watch  and inclrom IUCN . We obtarom IUCN , 43, whirom IUCN ). We estrom IUCN . We alsosolution . We thenCombined, the Pan-Borneo Highway and hydroelectric dams will affect 32 protected areas in Sarawak. The Highway will dissect three protected areas and 24 more protected areas will be within 25 km of the highway. Three additional protected areas are within the development periphery of the dams and four more protected areas are within the 25-km radius of the dams .Rheithrosciurus macrotis) which is only found in Borneo [Rafflesia) [Notably, an ~11 km section of the highway will traverse the Samunsan Wildlife Sanctuary in western Sarawak—the oldest wildlife sanctuary in Sarawak and home to the endangered proboscis monkey and critically endangered Sarawak surili . The Wiln Borneo . An ~8 kfflesia) . The Lanfflesia) . The LimUlu Air, Linau and Tutoh hydroelectric dams will be located within the territorial boundary of the Batang Ai, Hosa-Laga and Gunung Mulu protected areas respectively . Lanjak The Pan-Borneo Highway and hydroelectric dams in Sarawak will reduce current forest connectivity and the area of core forest substantially. Using a conservative consideration that the highway will impact only on the 1-km spatial extent buffering the road, ~18,500 ha of connectivity forest and ~5,200 ha of core forest would be lost . Again aOur analysis suggests that five segments of the highway will pose a critical threat to connectivity forest and core forest  and thus having large carbon stocks . AssuminMore than 55 km of the Pan-Borneo Highway in Sarawak will traverse peatland, including ~39 km in deep and very deep peatland (> 3m) areas. A number of road segments will impact peatland habitats—such as a ~30 km and a ~50 km road section in Limbang  followed by Baram , Limbang , Linau  and Tutoh dam . Ulu Air dam will impact the highest amount of area currently containing primary forest  followed by Tutoh  and Limbang dam  .The current route of the Pan-Borneo Highway will likely result in increased landslides in Sarawak. By mapping the highway against slope and total rainfall in the wettest quarter Figs  and 7, oMany planned and ongoing hydroelectric dams in Sarawak will also increase landslides in the region. If dam construction proceeds as planned, all dams will be constructed in currently forested areas and will inundate forest growing on steep slopes Figs  and 6. WThe above mentioned implications will greatly increase the maintenance cost of the highway and relevant disaster-management costs in the region in the post-hydroelectric dams’ development. The relevant organization such as Sarawak Government should consider to trigger a full cost-benefit analysis of the projects considering the maintenance cost of the roads and dam projects and associated disaster-management costs.Borneo is one of the richest biodiversity strongholds on the planet. The Pan-Borneo Highway and hydroelectric dams in Sarawak substantially threaten the remaining biodiversity of the region through several means—direct habitat loss through forest clearing, forest inundation, dissecting protected areas and key habitats, habitat fragmentation, core-forest degradation, and habitat isolation Figs , 3 and 5Many wildlife species will become more vulnerable to population loss under the planned projects, greatly increasing local extinction risk, including of several globally endangered species: proboscis monkey, Bornean orangutans and Sarawak surili. The highway would threaten the remaining protected key habitats of proboscis monkey in Sarawak—Samunsan, Limbang and Lawas protected areas—and a key protected habitat of the Sarawak surili, Samunsan protected area . In factPongo abelii) and African forest elephants (Loxodonta cyclotis) whose populations declined substantially due in part to road incursions in their habitat and resultant their habitat clearance mostly by illegal logging and deforestation [Apart from such habitat loss and degradation as mentioned above, the wildlife population in the region would also suffer from the increased access to the region the infrastructure would provide to subsistence hunters and poachers and, post-construction, an increased chance of wildlife vehicle collisions. A drastic decline of the population of many wildlife species in the region caused by hunting is evident , 54. Theestation , 56. Habestation . It is eestation .The extent of Bornean forest has been declining at an alarming rate since industrial development on the island . The ideLowland forest in Sarawak has experienced extensive clearing due to previous developments. Therefore, most of the primary forest and selectively-logged forests in Sarawak are restricted to the upland areas . These uMalaysia is working to expand its protected-area network and has stressed in its official planning documents that an effective protected-area network is the backbone of sustainable biodiversity and ecosystem service management in Borneo . Our resIn addition to several key protected areas for endangered species (mentioned in the above biodiversity section), some protected areas that would be impacted from these infrastructure projects such as Batang Ai and Lanjak Entimau extend into Indonesian Borneo . As such3 of forest biomass [The current infrastructure expansion projects in Sarawak do not appear to factor in climate change threats as they would increase both the carbon footprint and ecosystem vulnerability to climate change of the region Figs  and 5. T biomass .Second, several sections of the Pan-Borneo Highway will traverse large tracts of peatland . Road coThird, as each dam would inundate thousands of hectares of forest . These fThe planned and ongoing infrastructure expansion projects would increase the vulnerability of plant and animal species to climate change by reducing forest connectivity, core forest habitat and habitat degradation Figs , 3 and 5The highway would also reduce connectivity forest that currently connects several small patches of core forest areas vital for climate change adaptation measures for a number of globally endangered species in Borneo such as proboscis monkey, Sarawak surili and Bornean orangutan . Apart fSeveral sections of the highway and a number of dams would potentially foment long-term unsustainability in Sarawak and beyond. In addition to the likely cost to biodiversity, forest cover, and climate change mitigation, as discussed above, several ongoing economic and social challenges are also plausible in the context of infrastructure development.Road construction costs in tropical areas like Borneo are usually high due to environmental factors . MoreoveThe highway segments and dams in upstream forested areas Figs  and 7 maSome of the infrastructure expansion projects may cause long-lasting social stress, particularly in indigenous communities. It can happen in various forms such as involuntary displacement from ancestral lands and generational poverty, cultural changes, limited availability of long-practiced livelihood activities, and frayed social relationships , 72. WhiThe highway segments that will traverse protected areas, key habitat of threatened species and peatlands should be cancelled. These specifically include the road segments in the periphery of Samunsan, Gunung Gading, Lambir Hills, Limbang mangrove and Lawas mangrove protected areas, and the road sections in the periphery of the peatland in Miri, Sibu, Sri Aman and Samarahan regions. If the construction of these road segments is necessary for the development connectivity in the region then re-routing of the current routes through already cleared non-peatland areas is highly advisable.The road segments set to traverse unprotected primary or selectively-logged forest, connectivity forest and core forest areas should be considered as environmentally highly-risky. These include road segments between Telok Melano and Kuching, Sibu and Bintulu, Sri Aman, Miri and Lambir regions. These road segments should only proceed under tightly enforced and appropriate impact mitigation strategies such as declaring relevant zones as protected areas prior to road construction and increased environmental and social law enforcement thereafter.The road segments set to traverse forest areas with steep slopes (>20 degree) and high rainfall  should be cancelled, greatly minimized or reconsidered in light of landslide hazards. These areas include road sections between Telok Melano and Kuching, Sibu and Bintulu and Lambing regions. Such road sections would entail high construction and maintenance cost and jeopardise livelihood, water quality, and ecosystem services for downstream populations.Very recently, the government plans to re-route the Pan-Borneo highway section in northern Sarawak so as to now go around Brunei thereby connecting Miri, Marudi, Limbang and Lawas. If this re-routing proceeds as currently initiated, the re-routed section would likely have an even bigger environmental impact in the region than as analysed and reported in the current study as the section would cut through the largest remaining and connected forest in northern Sarawak. As such, the re-routing of this section should not be considered as a viable option due to environmental concerns.The master plan of hydroelectric dam construction in Sarawak needs to be reviewed in accordance with the extensive potential impacts that could occur from each dam. Clearly, the current plans for the hydroelectric dams construction in Sarawak have considered neither the unique environmental values of the landscape nor long-term overall sustainability of the projects. Under these values, several hydroelectric dam plans appear unviable and should be cancelled including Tutoh, Limbang, Lawas, Baram, Linau, Ulu Air and Baleh dams.Finally, a full cost-benefit appraisal of the development projects should be undertaken by the relevant authority, such as Sarawak State Government. Such an appraisal should include not only construction costs and environmental costs but also the long-term costs of maintenance for the highway and hydroelectric dams, relevant disaster management , and support services for the wellbeing of relocated communities including indigenous communities.Borneo forests possess both high conservation and natural-resource values. So, development projects in Borneo need to be less destructive for the environment, economically feasible—with low construction and maintenance costs—and socially acceptable—supporting the aspirations of local communities. Our results suggest that the current infrastructure expansion projects in Sarawak have overlooked the high conservation value of Borneo forests, climate change implications in the region, social aspirations, and the projects’ overall economic feasibility and long-term sustainability. Therefore, we suggest the following based on our analyses:


Bioengineering systems have transformed scientific knowledge of cellular behaviors in the nervous system (NS) and pioneered innovative, regenerative therapies to treat adult neural disorders. Microscale systems with characteristic lengths of single to hundreds of microns have examined the development and specialized behaviors of numerous neuromuscular and neurosensory components of the NS. The visual system is comprised of the eye sensory organ and its connecting pathways to the visual cortex. Significant vision loss arises from dysfunction in the retina, the photosensitive tissue at the eye posterior that achieves phototransduction of light to form images in the brain. Retinal regenerative medicine has embraced microfluidic technologies to manipulate stem-like cells for transplantation therapies, where de/differentiated cells are introduced within adult tissue to replace dysfunctional or damaged neurons. Microfluidic systems coupled with stem cell biology and biomaterials have produced exciting advances to restore vision. The current article reviews contemporary microfluidic technologies and microfluidics-enhanced bioassays, developed to interrogate cellular responses to adult retinal cues. The focus is on applications of microfluidics and microscale assays within mammalian sensory retina, or neuro retina, comprised of five types of retinal neurons  and one neuroglia (Müller), but excludes the non-sensory, retinal pigmented epithelium. Biomedical research has embraced microscale and microfluidic technologies to examine cellular behaviors and their responses to endogenous and therapeutic stimuli ,2. TheseMicrofluidics have been classically defined as systems that manipulate and interrogate sub-microliter volumes (μL) of fluid within engineered structures of critical lengths less than 1000 microns (μm), or 1 millimeter (mm) . This muMicrofluidic and microscale technologies has been applied to examine NS development and function in animal models from invertebrates to humans. The central nervous system (CNS) consists of the brain and spinal cord, responsible for higher cognitive function, learning, and memory. While, the peripheral nervous system (PNS) encompasses the nerves outside of the brain and spinal cord that connect to muscles and organs for sensory-motor function. In addition, primary senses act through the CNS to stimulate different centers of the brain that facilitate detection and processing. For instance, sound waves are collected by the cochlea of the inner ear, where the cochlear nerve carries auditory sensory information directly to the brain . OdorantRecent entries in the databases of the Web of Science and National Library of Medicine (PubMed) demonstrate an exponential rise of projects applying microfluidic and microscale technologies to study the brain, spinal cord, and its neuromuscular and neurosensory components, as shown in The World Health Organization (WHO) estimates that an unprecedented 350 million adults will develop severe visual impairment by the year 2050 . HoweverSignificant vision loss arises from dysfunction in the retina at the eye posterior, a photosensitive tissue connected directly to the brain through the optic nerve. Three retinal degenerative diseases constitute the majority of adult vision loss worldwide, as shown in Today’s regenerative projects combine stem-like cells and biomaterials with electro/physiochemical fields and biochemical factors to achieve tissue renewal. Microfluidic and microscale systems have modeled physiological scale and function across the NS , as wellTransplantation of retinal stem cells offers exceptional promise for restoring vision, as mature retinal neurons are unable to self-repair and hasten vision loss by propagating synaptic dysfunction via complex cellular interconnectivity. The retina is an excellent tissue target because its micrometer dimensions permit use of microliter volumes of reagents and lower numbers of replacement cells than other components of the NS ,121. MorDevelopmental biology has rapidly adapted the advantages of microfluidics to manipulate stem cell differentiation along pathways desired for regeneration. Recent projects have examined stem cell lineage progression via organoid models, i.e., simplified, microfluidic 3D organ culture systems that illustrate self-organized, cellular anatomy . ContempThe current article reviews microscale technology and microfluidics-enhanced bioassays developed to examine retinal cell behaviors in adult retina. This manuscript highlights technologies that leverage micrometer scales and (sub) microliter volumes to interrogate cellular responses critical to regeneration. MEMS  technologies developed for implantable prostheses , indepenVision is the detection and interpretation of light (defined as electromagnetic waves or photons) to produce images of objects in the brain. Light is absorbed and converted into electrochemical signals through the visual system, a part of the CNS comprised of the visual cortex, optic chasm, optic miasma, and the eye sensory organ, as per The path of incident light through the different components of the eye is shown in Mammalian retina is a multi-laminated structure populated by an interconnected network of millions of neurons and glia, as per The neuro retina is a laminated structure comprised of three layers of interconnected cells that communicate across two plexiform layers for signal transmission  as per . The out. Age-related macular degeneration (AMD) is a visual impairment that causes loss of central but not peripheral vision over time. Fine details of image processing are progressively lost, irrespective of observation from close or afar. The blurred images caused by AMD worsen with time to severely impact vision and quality of life with age. AMD occurs at the interface between photoreceptors and the RPE to reduce oxygen supply, nutrient support, and maintenance of neurons and epithelium [Millions of mature and aging adults experience progressive vision loss from retinal degeneration and injury, worldwide. The incidence of three primary retinal disorders alone is projected to increase four-fold by the year 2050 as per . Age-relithelium . AMD patithelium . Wet AMDithelium , i.e., iithelium .Diabetic retinopathy in adulthood affects three quarters of people diagnosed with diabetes, a chronic condition that alters the way the body processes glucose and/or produces insulin, the hormone that regulates blood sugar levels . DiabeteGlaucoma is a group of neurodegenerative diseases where damage to the optic nerve leads to progressive and irreversible blindness via loss of peripheral vision and contrast sensitivity . The mosModern diagnoses of retinal disorders have been enriched by translational imaging modalities, biomimetic materials, and engineered tissue constructs. Microfluidics in regenerative medicine now enable singular opportunities for quantitative study of retinal cell responses to a range of therapeutic and clinically-applied stimuli. Forthcoming sections of this article describe both the microfluidic assays and microscale studies developed to elucidate fundamental cell behaviors and collective responses needed to restore vision.A variety of in vitro assays have been developed or miniaturized in recent decades to examine the processes of intra- and extra-cellular signaling in retinal homeostasis and dysregulation, as well as to evaluate externally-applied stimuli to treat retinal disease . MicroflRetinal neurons and Müller glia have been examined, in large part, through in vitro cell culture, where surface-treated flasks or dishes are used to grow and observe cells outside of the body. Protocols of cell culture have been focal to the maintenance of primary retinal cells isolated from a wide range of animal models and clinical samples for over a half century . In vitrThe classic cell culture model is the static two-dimensional (2D) system developed nearly a century ago ,166. In Commercial miniaturization of static 2D culture systems leveraged the lower costs and increased adaptability of microfabrication technologies to manipulate (sub) microliter volumes of specialized reagents. These new micro-culture systems permit study of single or multiple cell groups, in parallel, with the added benefit of minimized reagent quantities. Contemporary 2D cell culture is, thus, now readily performed in microchambers, where microfluidic volumes are enclosed directly upon a microscope slide to enable the growth of cell groups on the slide itself. Large scale parallelization of microchambers yielded multi-well and microtiter plates, where hundreds to thousands of (sub) microliter compartments, or wells, are fabricated in a uniform footprint on a single substrate . It is nCompartments of microliter volumes have been widely-used to measure numbers of cells that migrate in response to extracellular signaling from one chamber to another. Traditional assays, such as Boyden or Dunn chambers ,169,170,Microfabrication processes developed for other areas of engineering, such as semi-conductor and electronics, have notably enhanced the in vitro study of cells via surface micro-patterning, i.e., the processes by which precisely-textured arrays of targeted biomolecules are created atop cellular substrates. Micro-patterned systems have been increasingly used to examine surface effects on localized cell response in biotechnology and regenerative medicine. Patterns are produced using (sub) micrometer features that are deposited or etched onto rigid or flexible substrates, such as silicon or elastomers, and functionalized with a variety of extracellular proteins and matrixes. These substrates are developed to stimulate changes in cell responses to a range of physiochemical stimuli significant to NS function, such as substrate rigidity and adhesion sites . Micro-pMicro-manufacturing from computer chip applications have been similarly applied to produce microfluidic channels with anatomical dimensions and geometries on the micrometer scale of biological systems. These microfluidic devices are manufactured using conventional photolithography on wafer substrates to create durable and reproducible molds, or through so-called soft lithography, using polymeric substrates to create more pliable and cost effective elastomers that interface with biological components, such as cells and tissues . In bothProjects in regenerative medicine have begun to apply long-term culture within microscale perfusion chambers to isolate and characterize potential replacement cells . PerfusiMicrofluidic channels have been parallelized and interconnected to facilitate increased complexity in the in vitro modeling of tissues . On-a-chMicrofluidic devices and in vitro assays have been indispensable in the development and advancement of regenerative medicine in the retina. Microtechnology has enabled ground breaking opportunities for the study and manipulation of stem cells, and become equally transformative in the study of stem cell responses to adult retinal cues needed for regeneration.Multifaceted cell behaviors are fundamental to the development and growth of retinal tissue, as well as to its pathology, disease progression, and response to insult and injury. Regenerative medicine seeks to restore vision, in part, by recapitulating endogenous cell processes essential for retinal function. These include behaviors, such as survival and death, adhesion and migration, as well as more specialized processes of intercellular connectivity and synapse. Descriptions of select microfluidic and microscale assays are shown in Survival of retinal cells outside of the body is critical to the in vitro methodologies on which development of many regenerative strategies rely. The long-term viability of replacement cells in vivo is essential because it facilitates the synaptic integration desired to restore vision. However, these replacement cells must survive isolation, characterization, and manipulation in vitro prior to in vivo application . NumerouIn vitro cell morphology has become increasingly significant to regenerative medicine, as cell shape is believed to portend intrinsic determinants of endogenous cell growth and repair processes ,199. MorIn vitro, microscale study of amacrine cells have provided an excellent model system with which to study intrinsic determinants of cell growth because of amacrine morphologic heterogeneity. Microscale systems, such as micro-wells and microstructures upon optical substrates, have greatly enhanced the ease of cellular imaging at increasing resolution to now characterize cell morphology using multiple parameters on the micro and nanoscale. Amacrine cells exhibit a widely varied and complex neurite patterning, with over 30 morphologic subtypes that include few to multiple neurites, short or long axon-like processes, and thin or bushy dendritic-like trees . It is bRod bipolar cells are similarly significant to retinal regeneration because they connect directly to photoreceptors to aid transmission of photonic signals . MicroscRetinal ganglion cells have been extensively studied in regenerative medicine because of their direct relationship with the optic nerve. Mammalian retinal ganglion cells consist of over a dozen subtypes, each clearly distinguishable from one another in structure and function. A recent study used micro-patterning to direct neuronal growth of ganglion cells for single cell stimulation . ExperimMicro-fabricated structures have also been used to examine the shape or size of retinal stem cells isolated for cell replacement therapy. A recent study  developeMany cell replacement therapies rely on the localized migration of transplanted retinal progenitor cells within host tissue for synaptic integration. Importantly, recent landmark studies illustrating material transfer from transplanted progenitors to models of genetic retinal disease have, thus far, reported the absence of this phenomena in transplantation to degenerated, adult retina . While, l-lysine, fibronectin, laminin, hyaluronic acid, and Matrigel to show different adhesion patterns upon each polymer surface. Tests further applied a chemical gradient along functionalized surfaces to examine progenitor chemotaxis. The results illustrated that constituent proteins of transplantable materials promoted individual or collective cell migratory behaviors to the same stimulus. Numerous biomaterials have since been developed to examine substrate-induced migration by using polymeric compounds of proteins endogenous to the inter-photoreceptor matrix and retinal extracellular matrix, such as hyaluronic acid, collagen, chondroitin sulfate, and laminin. While, emerging transplantable biomaterials have generated excitement to bolster outcomes of cell replacement therapy, their tissue engineering methodologies rely largely upon chemical interactions rather than microfluidics with the notable exceptions of microfabricated scaffolds. The reader is, here, directed to current reviews of emerging retinal biomaterials [Retinal progenitor migration was examined in early ophthalmic studies via microscale diode lasers during photocoagulation, i.e., processes that use heat to shrink or destroy abnormal retinal structures. One project reported that laser injury promoted migration and integration of retinal progenitor cells into host retina , which paterials ,216.Retinal cell migration has been most recently measured using chemotaxis and transwell chambers produced via microfluidics. These contemporary systems permit the study of cell morphology changes during substrate adhesion and motility, as well as signaling pathways activated in response to chemoattractive gradients. One study developed microfluidic transwell inserts that generated tissue culture-friendly gradients within multi-well plates . The selPrecise manipulation of the cell microenvironment within local segments of microfluidic channels facilitates measurement of different parameters to evaluate cell migratory behaviors, such as directionality of motion, cell polarization, path length, and net distance traveled. Moreover, these metrics are readily assessed by plotting real time cell trajectories against concentration gradients within the channel to facilitate more comprehensive study of cell migration than the cell numbers provided by transwell assays alone. A recent microfluidic chemotaxis chamber was developed to evaluate progenitor chemotaxis in response to a panel of extracellular growth factors . This syA microfluidic model of mammalian retina was produced using anatomical geometry and micrometer dimensions reported from mouse and human , as showFollow-up studies from this group then adapted a micro-nanofluidic system ,222, calNewer microfluidic studies have begun to examine the migratory roles of Müller glia in retinopathies driven by chronic metabolic syndromes, such as adult diabetes. As microfluidic transwell assays have illustrated chemotactic behaviors of Müller glia towards endothelial-associated factors, such as transforming growth factor beta (TGF-b) and fibroblast growth factor (FGF) ,226 a reApoptosis is the genetically-regulated process of cell death in multicellular organisms. Programmed cell death is central to the pathology of many retinal diseases and critical to development during retinogenesis. In adult tissue, apoptosis propagates biochemical stimuli that dysregulate retinal homeostasis and accelerate degeneration via cell to cell connectivity . A recen2+) and nitric oxide (NO) production through activation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor, resulting in the apoptosis of these secondary retinal neurons. A separate study used multiwell plates to illustrate that chronic light exposure to short wavelength, blue light (450–485 nm) can cause cell death in photoreceptor models via elevated mitochondrial metabolism [The apoptosis of primary rod and cone neurons via chronic light exposure has become heavily investigated in response to our hyper-exposure to illuminated screens via smart phones, tablets, and laptops . The rettabolism . Microfltabolism  to examiApoptosis of retinal ganglion cells from chronic degeneration has also been examined using multi-well plates. One study demonstrated that short wavelength blue light negatively affected mitochondrial function in retinal ganglion cells to decrease survival. Interestingly, subsequent exposure to long wavelength, red light enhanced mitochondrial function to increase survival of cultured retinal ganglion cells  and reduMicrofluidic systems have additionally examined the apoptosis of retinal ganglion cells due to chronically elevated intraocular pressure, a hallmark of glaucoma . As hydrVision requires extraordinary coordinated responses among retinal neurons and glia to produce images of objects in the visual cortex. Replacement cells must, therefore, possess specialized capabilities to establish cellular interconnectivity within existing retinal circuitry to restore vision. A variety of micropatterned substrates have examined cell to cell connectivity between primary neurons, interneurons, and retinal ganglion. A recent project  developeMicropatterned systems have also investigated how synaptic communication with retinal stem cells is influenced by the regional cell origin . RegionaMicrofluidic channels have similarly examined the cell-cell interactions needed for synapse formation between retinal neurons. One study developed a neural network chip, called the NN-Chip, as per A different project examined retinal synapse across retinal progenitor cells cultured within a multi-channel, microfluidic chip . GlycineRetinal glia are mechanosensors that maintain homeostasis as well as initiate neuroprotective responses to retinal insults. Müller glia are well known to ensheath retinal vasculature, provide nutrients and neurotransmitters, and act as light scattering cells for enhanced visual acuity ,189. HowOne study used microfluidic culture wells to examine the significance of interactions between Müller glia-retinal ganglion cells as a function of lactate . The retMicroscale technologies were additionally applied to examine behaviors of Müller glia significant to the neuritogenesis of retinal ganglion cells. In one study , Müller 2O2) injury [A separate study used microdevices to investigate the specific reaction of Müller glia and neurons to oxidative damage induced by hydrogen peroxide (H) injury . Via sep) injury . The stu) injury ,256,257.Microscale technologies have further examined cellular process and connectivity affected by changes in blood glucose levels. Elevated glucose concentrations can lead to the onset of adult diabetic retinopathies, which have been rising steadily worldwide and sharply in the United States . One stuContemporary microfluidics have evolved into lab-on-a-chip devices, where whole or tissue segments can be examined in a microfluidically-controlled environment. A recent retina-on-a-chip device was developed to facilitate the culture, manipulation, and probing of explanted tissue . The desA fundamental goal of cell replacement therapy is to restore vision by using stem like cells to replace dysfunctional or damaged cells. The development of replacement cells has been transformed through the bioengineering manipulation of endogenous, somatic, and induced pluripotent stem cells ,266. HowGuidance of neuronal growth cones is an essential component of retinogenesis and regeneration, as these cellular extensions are the primary seekers of synaptic targets in neural tissues. Growth cone guidance of retinal neurons has been examined in microfluidic systems able to produce controllable gradients of extracellular molecules. One project produced a chip of microfluidic networks, called the microFN, to deliver different concentrations of the axonal guidance molecule, ephrinA5 . The micMicrofluidic perfusion has been applied to manipulate the diffusive signaling of cell-secreted factors that regulate the cell fate of mouse embryonic stem cells (mESCs). In one project , microflMicrotechnology has been similarly applied to study retinal differentiation using topographical cues. One study developed a biodegradable polycaprolactone (PCL) thin film scaffold with microfabricated topography to enhance the attachment and organization of retinal progenitor cells . The proAnother project used soft lithography-patterned poly (lactic-co-glycolic acid) scaffolds (PLGA) to guide the morphogenesis of retinal cells derived from both human embryonic stem cells (hESCs) and dissociated newborn mouse retinas . The proMicropatterned substrates were recently used to affect the differentiation and behavior of human neural progenitors in the developing retina . MicropaThe innovation of 3D microstructured scaffolds has dramatically altered delivery of replacement cells into adult retina ,282. MicMicrofluidic technologies have transformed contemporary understanding of retinal cell processes and helped apply this newfound knowledge to cultivate regenerative strategies for adult retinal disorders. Persistent challenges in cell replacement therapy, however, require new microfluidic models and bioassays.One significant hindrance to retinal cell replacement is the lack of retinal models with similar critical characteristics of the human eye. While mouse models have produced outstanding contributions to bioengineering in the visual system, and beyond, the rodent retina is rich in rod photoreceptors used for night vision, but low in cone photoreceptors needed for visual acuity. Moreover, the rodent retina lacks a macula, where cone cells reside and most vision loss originates. Microfluidics, designed to create a cone-enriched environment, and/or macula-like structure, will greatly aid the study of cone pathology and degeneration to support integration during cell replacement therapy ,211.Significant microfluidic contributions to regenerative medicine can also be made via systems able to examine adult, collective cellular responses. Although, miniaturized bioassays have elucidated a wealth of behaviors from individual retinal cell groups , mechanisms of cooperative response between multiple neuronal groups, with and without glia, remain incompletely understood. Integrated cellular responses of mature retinal networks is especially significant to cell replacement therapy because endogenous neurons are likely to respond collectively to stem-like cells transplanted to replace dysfunctional components. Future directions for microfluidics also include the design of comprehensive cellular models for the retinal blood barrier, both the outer barrier formed at the RPE and the inner barrier at the retinal anterior. Although select microfluidic models of the retinal blood barrier exist ,129,261,Microfluidic technologies multiplexed into micro-physiological systems (MPS), or organoid models, have endowed transformative opportunities to examine and manipulate retinogenesis via genetic modifications, enriched extracellular matrix, and external cues and signaling fields, such as chemical gradients and electrical stimulus. However, these 3D models mimic developing retinal tissue produced using stem cells, which create substantially different cues than mature and/or degenerated retina in adults. Future MPS study is needed to incorporate adult retinal cells, such as Müller glia or ganglion cells, to develop hybrid, or blended, in vitro models able to guide emerging therapies for adult tissue more appropriately.Lastly, the community is in need of novel microfluidic and macroscale systems to augment parallel testing models. While multi-well substrates have provided critical information about cell response to different external growth factors and pharma-compounds, microfluidic systems designed to manipulate and examine multiple explants or inoculated eyes remains underdeveloped. Such “assistive” microfluidic technologies will help empower translation of therapies from cellular samples to retinal explants, and organoid retinal models to adult retina. The examination of different responses from each biological component to the same stimulus will greatly elucidate the behaviors of adult tissues needed for regeneration.In summary, while microfluidic contributions have bolstered a revolution in neuro-regenerative medicine, many opportunities remain to interrogate the specialized behaviors of mature cells and thecomplexity of adult cues from healthy and damaged tissue. Moreover, quantitative, microscale study of cellular interconnectivity between endogenous and de/differentiated replacement cells will significantly advance current understanding of thesequence and nature of synaptic integration processes needed for functional stem cell cell replacement.


Rapid-acting interventions for the suicide crisis have the potential to transform treatment. In addition, recent innovations in suicide research methods may similarly expand our understanding of the psychological and neurobiological correlates of suicidal thoughts and behaviors. This review discusses the limitations and challenges associated with current methods of suicide risk assessment and presents new techniques currently being developed to measure rapid changes in suicidal thoughts and behavior. These novel assessment strategies include ecological momentary assessment, digital phenotyping, cognitive and implicit bias metrics, and neuroimaging paradigms and analysis methodologies to identify neural circuits associated with suicide risk. This review is intended to both describe the current state of our ability to assess rapid changes in suicide risk as well as to explore future directions for clinical, neurobiological, and computational markers research in suicide-focused clinical trials. The suicide crisis is a psychiatric emergency, and roughly 900,000 Americans present to the emergency department each year for suicidal thoughts and behaviors . In thisThe existing armamentarium of traditional suicide treatments includes lithium , clozapiWhile these interventions have the potential to transform the clinical treatment landscape for suicidal individuals, there is also a tremendous research opportunity associated with their use. Specifically, the need to measure the efficacy of rapid interventions has the potential to spur researchers to develop new tools and techniques for use in next-generation clinical trials, with particular emphasis on assessing moment-to-moment changes in suicidal ideation/behaviors using novel digital, neuroimaging, and computational methodologies. In this context, clinical trials of rapid-acting interventions permit the incorporation of biomarkers throughout the study design in an experimental therapeutics approach. For example, innovative assessments, tasks, and neuroimaging methods can be measured both at baseline and after intervention/placebo to examine potential biomarkers of response. Such an approach, which has already been implemented in rapid-acting clinical trials for depression , has theThis review will discuss new directions in the assessment of rapid changes in suicide ideation (SI) and suicide risk. The review begins by discussing concerns related to the current way that rapid changes in SI are clinically assessed. Three emerging areas within the suicide risk literature will then be described that could be used to measure efficacy in future clinical trials of rapid-acting antisuicidal agents. These include: (1) ecological momentary assessment (EMA) and digital phenotyping approaches for identifying real-time markers of change in SI and risk factors; (2) cognitive markers of suicide risk, including implicit biases and markers of decision-making associated with suicide risk that could be used to support clinical trials of rapid-acting interventions; and (3) neurobiological markers of suicidal thoughts and risk that could be used to highlight potential avenues connecting SI to changes in specific neural circuitry.The literature regarding the assessment of rapid-acting interventions for suicide risk is limited by several factors. These include use of self-report measures to determine suicide risk and shortcomings associated with clinical risk assessments that are not designed to assess rapid changes in SI.First, suicide assessment instruments predominately rely on the participant's report of SI and suicidal urges. This type of assessment of SI and behaviors introduces extra obstacles that may obscure a complete understanding of the current level of suicide risk. For example, individuals may minimize suicidal thoughts due to concerns about stigma, treatment by healthcare professionals, or hospitalization . Those fSecond, in addition to relying on self-report measures, few, if any, of the suicide assessment instruments were developed to repeatedly assess rapid changes in suicidal symptoms over short periods of time. For example, most of the literature exploring the anti-suicidal effects of ketamine used single items from the Montgomery-Åsberg Depression Rating Scale   and the As a result of these limitations, it has been difficult to link suicidal thoughts and behaviors with specific pathophysiologies. While candidate endophenotypes have been suggested , to dateOver the last decade, research using EMA on mobile devices has become more prevalent as a method of assessing rapid changes in suicide risk. Unlike the more traditional clinical rating scales discussed above, EMA allows rapid changes in suicide risk to be measured through real-time monitoring of changes in SI and behaviors over time.In EMA, specific items are queried several times a day following a scheduled signal from the device or around moments of distress or specific thoughts and behaviors. Items can include symptoms such as depressed mood, anxiety, suicidal thoughts, as well as physical or social factors such as sleep, physical activity, or social interactions , 31. BecIn addition, EMA research can address the interplay between suicide risk factors as well as how symptoms fluctuate over the course of days or even hours. In one EMA study of adults with recent suicidal behaviors, suicide risk factors such as hopelessness, burdensomeness, and loneliness were found to vary significantly throughout the day; however, these risk factors did not predict changes in SI within a time span of 4 to 8 h . In contGiven the amount of data collected across many timepoints in EMA datasets, researchers have been using new analytic techniques to better characterize suicide risk. For example, Rath and colleagues examined EMA data using network analysis to understand the relationships between psychological risk factors and SI within short blocks of time (30–120 min) by administering 10 EMAs per day . AnotherAnother relatively new way of making sense of large EMA datasets and other real-time monitoring data is digital phenotyping, which is the identification of patterns in data drawn from a variety of sources, including mobile devices, GPS, speech samples, internet and social media activity, keyboard activity, and EMA –41. In aBeyond EMA, finding patterns in passively collected data has implications for detecting changes in suicide risk outside of participants' awareness, such as detection of smartphone movement, location, ambient light, or text messages . One stuIt should be noted that while ample evidence exists that EMA and digital phenotyping are feasible for studying suicidal thoughts and behaviors, there are also important limitations to consider. As with other types of measures, researchers must consider the role of self-report and insight in EMA data. When distress is high, participants may not be as likely to complete their EMAs, which may be critical to understanding risk in the context of rapid changes . SimilarDespite these limitations, EMA and real-time monitoring methods make it possible to study rapid changes in suicidal thoughts and behaviors, suicide risk, and associated symptoms without many of the limitations associated with traditional clinical measures. Digital phenotyping and machine learning approaches to this real-time monitoring data could be particularly useful in trials of rapid-acting interventions, both in identifying the efficacy of interventions and predicting who is likely to benefit. Future directions include the development of analytic techniques to interpret rapid changes in this complex data over the course of treatment. Although results from EMA and digital phenotyping approaches are unlikely to be as readily interpretable as results from clinical rating scales  they may nevertheless reveal latent suicide risk factors such as variability of SI or time spent in the suicidal state, which could serve as valuable metrics of treatment response in future clinical trials.Behavioral tasks are another way to assess suicide risk beyond self-report. Cognitive constructs such as impulsiveness and hopelessness have already been linked to suicide risk, primarily using self-report measures . BehavioThe most prominent examples of suicide-specific tasks are formulations of the Implicit Association Task (IAT). Although the IAT was initially developed in the social psychology literature, Nock and colleagues adapted it to measure both non-suicidal self-injury and associations between the self and death/life , 54. In Another area of study focuses on attentional biases to suicide-related stimuli, most easily represented by a formulation of the Stroop task with suicide-related stimuli. Specifically, in a “Suicide Stroop,” individuals are asked to name the color of suicide-related negative- or neutrally-valenced words. Initial results demonstrated that increased interference for suicide-related words—indicating a suicide attentional bias—was associated with increased risk for suicide attempt at 6-month follow-up as well as with recency of suicide attempt . HoweverIn summary, there is one suicide-specific task, the suicide IAT, which demonstrates initial utility for clinical trials due to its ability to predict later suicidal thoughts and behaviors, while also exhibiting sensitivity to treatment effects. Benefits of these cognitive or task-related approaches are that such tasks are usually relatively quick to administer, low-cost, easily scalable, and do not rely on direct report of suicide-related symptoms. Limitations include the complex nature of many of the tasks, which preclude associating task performance with specific neural circuits. As a result, new computational approaches that model specific task-performance features or components may be informative for assessing suicide risk. For example, in one recent study of the Iowa Gambling Task, Bayesian analysis of decision-making performance demonstrated that suicide attempters exhibited greater loss aversion than depressed controls or healthy volunteers ; similarSeveral neuroimaging studies have attempted to characterize SI from a neurobiological perspective. However, no studies to date have assessed rapid, hour-to-hour changes in SI, a significant limitation given the moment-to-moment variability of suicide risk reviewed above. Many studies that have assessed functional brain changes associated with suicide risk have characterized suicide risk using lifetime history of suicide attempt regardless of time since the most recent attempt. In addition, neuroimaging studies have typically characterized the neurobiology of SI or some metric of suicide risk using resting-state scans or tasks developed to assess correlates of mood disorders  rather than tasks developed to assess suicide risk directly. Finally, these studies have mostly assessed suicide risk in larger clinical samples of participants diagnosed with mood disorders –75 and oA recent comprehensive review of structural and functional brain changes accompanying suicidal thoughts and behaviors implicated the ventral and dorsal prefrontal cortex systems and their connections with insula, anterior cingulate, mesial temporal structures, striatal, and posterior connection sites with suicide risk . SubsequStudies in adolescents during rest have also found network-level changes associated with SI in overlapping brain regions. For example, decreased connectivity between the default mode, salience, and executive control networks was reported in adolescents who were currently experiencing depressive symptoms and had a history of suicide attempt, in addition to increased connectivity between the salience and executive control networks . LongituIn addition to measuring large-scale brain network dysregulation during rest, recent neuroimaging studies have also sought to measure neurobiological correlates of SI and suicide attempts in both adolescents and adults using novel tasks that measure social and decision-making processes, given that relational stress and impulsivity have been linked to suicide attempts , 83. OneDrug studies have also assessed neurobiological correlates of rapid-acting anti-suicidal treatment response in adults diagnosed with MDD, though more work is needed in this area to characterize the neurobiology associated with rapid changes in mood following drug administration. For example, changes in SI have been associated with changes in functional connectivity between the anterior cingulate, dorsolateral prefrontal cortex, and superior parietal cortex following administration of low (0.2 mg/kg) and standard (0.5 mg/kg) doses of subanesthetic ketamine . In partFinally, recent neuroimaging studies with healthy participants have attempted to assess brain regions associated with suicidal thoughts. For example, a recent study that used an adaptation of the suicide-related IAT found increased activity in the bilateral insula, middle occipital cortex, medial prefrontal cortex, and parahippocampal gyri in response to self-death compared to self-life associations . A seconTaken together, studies exploring the neurobiology of SI and suicidal behavior suggest that local and long-range brain network changes accompany suicide risk. However, significant limitations need to be addressed to better characterize these brain network changes. For example, neuroimaging studies of recent suicide attempters compared with non-attempters will help address acute risk. In addition, measuring neural correlates of cognitive tasks such as the suicide-related IAT will provide important insights into the relationship between suicide risk and network-level changes in brain circuitry, allowing for the characterization of the neurobiology of suicide risk independent of self-report clinical measures. Finally, advances in computational techniques such as the application of machine learning algorithms and mathematical models that characterize decision-making and reinforcement processes will allow for a more complete mechanistic account of the neurobiology of suicide risk.Previous research on suicide risk has relied on self-report measures that are not designed to capture rapid, moment-to-moment changes in SI. This impedes efforts to identify phenotypes and biomarkers of the suicidal state and hinders the development of individualized clinical care for those experiencing a current suicide crisis, underscoring the need for improved methodologies capable of capturing rapid changes in suicide risk. Each of the methods reviewed above—EMA, digital phenotyping, cognitive and implicit bias tasks, and candidate neuroimaging biomarkers—can improve our understanding of suicide risk beyond the dichotomy of “suicidal” or “not suicidal.” These methods also offer the potential to reveal whether treatments impact variability in SI, implicit suicide bias, and specific neural circuitry activity as a function of suicide-related stimuli.While research in this area is ongoing, there are obvious extensions to clinical treatment of patients. Specifically, clinicians have long known that suicide risk exists across a continuum and that active suicide risk ebbs and flows over time. Once these techniques are validated, one can picture how these tools can assist clinicians in monitoring their patients in both rapid-acting interventions or even traditional treatments such as lithium or psychotherapy. For example, digital assessments could provide real-time information about clinical symptomatology in high-risk patients; clinicians could be alerted if their patient has reported increased SI over time, mood fluctuations or reduced sleep as indicative of a “red flag” for active suicide risk. When treating a patient who denies SI, behavioral tasks could provide additional context around implicit suicide risk. Baseline EEG or fMRI scans could provide clues to which treatments might be most effective for a given patient. Therefore, these approaches may define new treatment avenues and lay the foundation for precision psychiatry for the treatment of suicidal individuals.All authors contributed equally to the literature search, writing, and revision of this manuscript. All authors approved the final version of the paper.CZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of -hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of -ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of -hydroxynorketamine and -hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.