In terms of natural hazard events, resilience characterizations provide a means of identifying risk profiles, degrees of preparedness, and the ability of communities to respond and recover. While nationally consistent measures of community resilience to natural hazards are needed to address widespread socio-ecological impacts from a broad policy perspective, geographically specific resilience characterizations are needed to target local resources to increase community resilience. The Climate Resilience index (CRSI) was developed to characterize the resilience of socio-ecological systems in the context of governance and risk to natural hazard events for all U.S. counties for the years 2000–2015. Those resilience characterizations were based on the full range of nationwide county domain scores. This paper presents a re-scaled application of CRSI, where county domain scores are limited to the range of scores within a specific set of U.S. coastal and shoreline counties within each of eight coastal regions. The re-scaled CRSI values for selected counties/parishes in the Gulf of Mexico (GOM) region are also presented in conjunction with calculated Location Quotients (LQ) values >1.0, which represent a high employment dependence on ocean economy sectors. Using a combination of re-scaled CRSI and LQ values provides a more holistic picture of vulnerability and resilience in these U.S. coastal shoreline counties. The relative resilience assessments presented for coastal regions are useful in identifying potential strengths and weaknesses in resilience aspects given similar hazard profiles, a signature otherwise diluted in nation-wide county-level assessments. The unique approach of combining CRSI and LQ for characterizing natural hazard resilience described could be transferred to other specific geographies as defined by population groups, hazard profiles and economic dependence. Resilience describes the ability of a system and its component parts to anticipate, absorb, accommodate or recover from the effects of a hazardous event in a timely and efficient manner . Within In terms of natural hazard events, resilience characterizations provide a means of identifying risk profiles, degrees of preparedness, and the ability of communities to respond and recover. General resilience strategies as described by From a policy perspective, there is a need for nationally consistent measures of community resilience that address the potential widespread socio-ecological impacts of natural hazard events. The Climate Resilience Screening Index (CRSI) is a composite measure for characterizing the resilience of SES in the context of governance and risk to natural hazard events. CRSI is a composite index, including five domains  made up of 20 indicators and 117 metrics . CRSI waThe CRSI approach is unique in that it addresses a combination of multiple hazards, governance, and, strengths and weaknesses in social, built and natural environments, for U.S. counties, boroughs and parishes nationwide. The structure of CRSI, the methods used to construct the index and the use of publicly available data lend themselves to a valid approach to rescaling for specific U.S. geographies. CRSI provides a comparative characterization of county-level resilience for all U.S. counties, thus permitting smaller evaluations of regions or states at the same broad comparative level, i.e., inclusive of all counties . This tyCRSI characterizes the appropriate components to identify communities based on their hazard profile and other characteristics; however, the individual metrics of CRSI have not been analyzed within specific geographic locations. These geographically specific characterizations are needed to inform local decision making. An example of such a geographic grouping of communities with similar hazard exposures is coastal areas, which have varying degrees of resilience within regions. Coastal areas face specific unique resilience challenges with increased vulnerability to human and natural threats. The multiple threats and impacts natural hazard events, like hurricanes, have raised concerns from policy makers, stakeholders and residents regarding the long-term viability of coastal communities .Evidence of the challenges to coastal resilience was demonstrated by two recent events, Hurricane Katrina and the Deepwater Horizon oil spill . CoastalIn context of social resilience, diversity of livelihoods may be an important factor in buffering the impacts of natural hazard events . LocatioThe nation-wide CRSI results provide a scale of assessment important for broad national policy development and targeting areas for improvement; however, it does not allow more in-depth assessments for areas that share common traits  or share smaller common boundaries . Similarly, the unscaled CRSI is a screening assessment and does not evaluate CRSI alongside other tools more specific to economic or quality of life information. To address these issues, CRSI analyses were rescaled to coastal regions and coupled with LQ values to characterize the differences among coastal counties. We differentiate and compare risk components and evaluate relative domain contributions to resilience within each of within each of eight coastal regions. For the Gulf of Mexico (GOM) region, we present CRSI values in conjunction with Location Quotients (LQ) based on ocean economy sector employment for a subset of coastal counties/parishes. The objective is to demonstrate the approach for rescaling CRSI for coastal areas and to present the potential value of a combined index approach to regionally characterize resilience for coastal counties with economic dependence on coastal resources.The dependence on ocean and Great Lakes economies and the specific set of hazard designations associated with U.S. coastal shoreline counties provides the set of coastal counties upon which CRSI was recalculated to characterize coastal shoreline counties’ resilience within the context of each of eight coastal regions. The re-scaled CRSI scores were then examined in relation to county dependence on the ocean economy as represented by the calculated location quotient (LQ) for the total ocean economy and six ocean sectors. In the GOM region, a subset of coastal counties with ocean economy LQ (LQ_OE) values >1.0 (high dependence on the ocean economy) were also characterized by examining levels of resilience (CRSI scores) along with calculated LQ values.1. The ENOW 2015 dataset includes 402 coastal shoreline and coastal counties in 30 coastal states in eight regions. The coastal shoreline counties in this data set are based on the Federal Emergency Management Agency’s designation requiring a coastal county to have a coastline bordering the open ocean or the Great Lakes, or contain coastal high hazard areas referred to as V-zones, special flood hazard areas or areas that are vulnerable to high velocity wave action from storms or seismic activity)2. The ENOW dataset excludes shore-adjacent counties with no relevant economic activity (11 counties and the District of Columbia) and includes 17 additional counties that are not shore-adjacent but do have significant ocean and Great Lakes economic dependence. Of the 402 counties in the ENOW dataset, CRSI metric data were available for 398 counties. Hereafter, these 398 counties will be referred to as ENOW coastal counties. Each county was assigned to an ENOW designated region to rescale CRSI for regional characterizations.The coastal and coastal shoreline counties identified for regional scaling of CRSI were selected from NOAA’s Economics: National Ocean Watch (ENOW) 2015 datasetThe number of counties within each region are as follows:Great Lakes (85)Gulf of Mexico (68)Mid-Atlantic (93)North Pacific (19)Northeast (28)Pacific (5)Southeast (53)West (47).Original CRSI resilience characterizations were for all U.S. counties for the years 2000–2015, scaled based on the full range of nationwide county scores. These national scale resilience characterizations are intended to provide information and results comparable across all U.S. counties and regions. We rescaled CRSI using the ENOW coastal counties and regions as identified above. The ENOW regional rescale for CRSI was done by limiting the range of metric values assessed to only those for counties within each of coastal region. ENOW coastal county CRSI results for the coastal regions are comparable only within each region. Re-scaled metric values were used to calculate indicator and domain scores following The Risk domain includes two indicators, exposure and loss. Metrics were derived as a probabilistic calculation based on geophysical and technological hazards as described in We calculated domain scores for each of the other four domains  from re-scaled metric scores. i = the value of CRSI or adjusted resilience for county i and Soc(a)i, BE(a)i, and NE(a)i are the adjustment multipliers for Society, Built Environment, and Natural Environment in each county i, and Riski is the Risk score for county i. The adjust factors are calculated as:i is the social domain score for county i and Socm is the median social domain score for all counties;I is the adjustment multiplier for built environment in county i, BEi is the built environment domain score for county i and BEm is the median built environment domain score for all counties;I is the adjustment multiplier for natural environment in county i, NEi is the natural environment domain score for county I and NEm is the median natural environment domain score for all counties.All domains for each ENOW coastal county were min-max standardized on a scale from 0.01 to 0.99. The final CRSI calculation begins as a scaled value for recoverability/vulnerability derived from Governance and Risk (basic CRSI) with the Governance value being adjusted by the remaining domain scores for social, built environment and natural environment to complete the calculation of CRSI as shown below:The distribution of ENOW coastal county CRSI scores within each coastal region was examined to identify domain level differences in county resilience characterizations and to compare natural hazards profiles. Regional coastal re-scale CRSI results were examined to look at top and bottom-ranked counties and to highlight domains positively and negatively influencing overall scores. CRSI scores for the GOM region were then supplemented with location quotients for the total ocean economy and ocean sectors to characterize potential socio-economic vulnerabilities specific to ENOW coastal counties.The CRSI Society domain includes an Economic Diversity indicator calculated from two metrics, the Gini coefficient and The Hachman Index . The Gin3.NOAA’s Economics: National Ocean Watch (ENOW) data includes employment data statistics derived from the Bureau of Labor Statistics’ Quarterly Census of Employment and Wages data. ENOW provides both employment data for Total Ocean Economy, and for the six ocean sectors it includesTotal Ocean Economy (OE)- All ocean economic activities within a geography.Living Resources (LR)- Commercial fishing, fish hatcheries, aquaculture, seafood processing, and seafood markets; recreational fishing is excluded (included in Tourism and Recreation).Marine Construction (MC)- Beach nourishment and harbor dredging.Ship and Boat Building (SBB)- Ship and boat building and repairs.Marine Transportation (MT)- Deep sea freight, marine passenger transportation, pipeline transportation, marine transportation services, search and navigation equipment, and warehousing.Offshore Mineral Extraction (OME)- Oil and gas exploration and production, and sand and gravel mining.Tourism and Recreation (TR)- Eating and drinking establishments, hotels, marinas, boat dealers and charters, campsites and RV parks, scenic water tours, manufacture of sporting goods, amusement and recreation services, recreational fishing, zoos, and aquariums.4 County total ocean economy employment data and employment data for the six ocean sectors were obtained from NOAA’s ENOW API5.Each of these six ocean sectors has specific North American Industry Classification System (NAICS) industry codes associated with it4z6 as a proportion of the ratio of the total employment in the ocean sector within the coastal region to the total employment in all ENOW coastal counties. In the calculation of each ocean sector LQ, the concentration of employment in each sector was compared to the concentration of that sector employment for all ENOW coastal counties within that region in context of total ocean economy employment for the region.An ocean economy location quotient (LQ_OE) for each of the ENOW coastal counties in the GOM Region was calculated based on the proportion of county employment in the ocean sector to the total employment in the countyLocation quotients for the ocean economy and the six sectors were calculated for each GOM ENOW coastal county as follows:i = county employment in the total ocean economy or ocean sector, e = total county employment for ocean economy LQ calculation or total county employment in ocean economy for ocean sector LQ calculations; Ei = GOM region employment in the ocean economy or sector; E = total GOM region employment for ocean economy LQ calculation or total GOM region employment in ocean economy for ocean sector LQ calculations.LQ = location quotient for the total ocean economy or sector (i); en = 42) within the GOM region with LQ_OE values > 1.0 were selected to examine employment dependence in context of resilience scores. First, all values were percentile ranked. Each county CRSI score and LQ_OE value was categorized using the median for each measure, as estimated from the subset of regional values. Counties with LQ_OE and CRSI values below the GOM regional median value were categorized as having lower ocean economic dependence and lower resilience. Counties with LQ_OE and CRSI values above the median for the regional subset were categorized as having higher ocean economic dependence and higher resilience. LQ_OE and CRSI percentile ranked values were plotted as a four-quadrant bubble plot displaying the degree of resilience and dependence on the ocean economy for a visual comparison.A subset of counties  are presented for each regional characterization . The topAmong the top-ranked CRSI scores in the counties of the Great Lakes region, risk domain scores were low (less risk), contributing to higher CRSI scores. For the lowest CRSI scores in the region, Risk domain scores were high and most counties ranked in the bottom five had lower scores in the Society domain. The highest and lowest Governance domain scores within the entire region were in Keweenaw County, MI and Erie County, PA respectively; both ranked in the bottom five for CRSI scores in the region. Keweenaw County, MI also had the lowest Society domain score for the entire region. Built Environment domain scores varied across the top and bottom-ranked counties. The majority of Natural Environment domain scores among the top and bottom-ranked counties fell within the upper 50th percentile range for the region.Governance domain scores were generally in the upper 50th percentile with the exceptions of Liberty, Gulf and Monroe counties in Florida. Monroe, Florida ranked last in the Governance domain among all GOM counties. Risk domain scores were lowest for the highest-ranking counties for CRSI, except Brazoria, TX, which had a higher Risk domain score than the other top five and bottom five counties except Orleans, LA. All ranked counties shown had Risk domain scores in the lower 25th percentile across the GOM region. Of the top and bottom ranked counties, only three had scores above the 50th percentile for the Built Environment domain. Counties with the lowest CRSI scores also scored low in the Society domain except Monroe County, Florida. Natural Environment domain scores for the top and bottom-ranked counties in the GOM were generally lower for the bottom-ranked counties except for Liberty County, FL.As seen within many of the regions, Risk domain scores were lowest among the top-ranking counties in the Mid-Atlantic region. However, both Salem County, NJ and Somerset County, MD scored low for Risk and scored among the bottom five ranked CRSI scores. Scores for the Built Environment, Society and Natural Environment domains were much lower for the bottom-ranked counties except Salem County, NJ and Somerset County, MD which scored highest among the ranked counties shown for the Natural Environment domain. Arlington County, VA ranked scored the lowest in the region for the Natural Environment domain. King William County, VA scored low for the Built Environment domain among the top five CRSI ranked counties. Governance domain scores shown for the ranked counties were all in upper 50th percentile for the region except Baltimore City, MD and Arlington County, VA.In the North Pacific region (Alaska), Kodiak Island Borough scored highest for CRSI and Bristol Bay Borough scored lowest. Risk domain scores among the highest and lowest ranked counties for CRSI were low except for Yakutat City Borough which scored the much higher (0.56). Governance domain scores varied across the counties shown with Bristol Bay Borough scoring the highest among the top and bottom-ranked counties and Wrangell City Borough scoring the lowest in the North Pacific region. These same two boroughs scored lowest in the region for the Built Environment domain. Society domain scores also varied across the top and bottom-ranked boroughs; however lower scores are shown for the Census Areas of Dillingham and Hoonah-Angoon and for the boroughs of Bristol Bay and Wrangell City. Natural Environment domain scores shown were all greater than the 50th percentile for the region with the Dillingham Census Area scoring highest within the North Pacific region.Hancock County, ME scored highest for CRSI in the Northeast region, while Nantucket County, MA scored lowest. Risk domain scores were lowest among the top-ranked CRSI counties in the Northeast region except Lincoln County, ME. Built Environment domain scores varied across the ranked counties shown with one of the top-ranked counties, Lincoln County, ME scoring low and Bristol, RI scored the lowest for this domain within the entire region. The lowest score within the region for the Governance domain was also shown for Bristol County, RI and the score was also low for New London County, CT. New London County also had the lowest Society domain score for the Northeast region; Lincoln County, ME the highest. All but two ranked counties, Strafford County, NH and Suffolk County, MA, scored above the regional mean for the Natural Environment domain.The highest Risk domain scores among the five counties of the Pacific region (HI) are shown for the two top CRSI ranked counties, Honolulu and Hawaii. Hawaii County had the highest Risk domain score for the region, but also scored highest for the Built Environment domain. Hawaii County scored highest in the region for the Society and Natural Environment domains. Maui scored low in the Natural Environment domain, as did Kauai County. Kauai County also scored lowest in the region for the Built Environment domain. Kalawao County scored lowest in this region for the domains of Governance, Society and the Natural Environment and also scored low in the Built Environment domain.Within the Southeast region, Pender County, NC scored highest for CRSI and Wayne County in GA scored lowest. All but two counties scored above the median for the Governance domain. Risk domain scores for the top and bottom-ranked counties in the region were all low. Only one ranked county shown, Pender County, NC, scored in the upper 50th percentile for the Built Environment domain. Lower Built Environment scores are shown for the bottom-ranked counties. Brantley County, GA scored lowest in the region for the Society domain and all bottom-ranked counties in the region scored lower for this domain. Similarly, Natural Environment domain scores for the lower ranked counties were all lower than those with the highest CRSI scores.The highest and lowest CRSI scores for the West region were in Clallam and Wahklakum Counties in WA, respectively. Higher Governance domain scores are shown for the counties that ranked lowest for CRSI in this region. Counties ranked in the bottom 5 for CRSI had higher Risk domain scores. Lower scores for the Built Environment, Society and Natural Environment domains are shown for most of the bottom-ranked counties with the exception of San Joaquin County, CA, which scored higher for the Built Environment domain and Del Norte County, CA which scored higher in the Natural Environment domain.Resilience characterizations within geographically, economically and socially similar areas may foster peer to peer transfer of best practices. For example, in the GOM region, Kenedy County, TX (CRSI = −22.2) might look to best practices in Victoria County, TX (CRSI = 107.8) for built environment, society, and natural environment activities to improve Kenedy County resilience. These two GOM counties have similar risk profiles. Similarly, in the Mid-Atlantic region, Somerset County, MD (CRSI = −1.75) and King William County, VA (CRSI = 23.89) have similar risk profiles but Somerset has significantly lower domain scores in all categories. King William County could provide Somerset with examples of actions that have enhanced King William’s governance, built and natural environments or social systems.The location quotients >1.0 for the total ocean economy (LQ_OE) and the corresponding ocean sector location quotients for GOM counties are included along with the CRSI scores . Forty tPercentile ranked LQ_OE, and CRSI scores for the forty-two ENOW coastal counties and parishes in the GOM region are plotted in As presented, counties falling in the lower right-hand quadrant should be considered more vulnerable compared to the other counties shown in the region. The counties in the upper left-hand quadrant (Lower LQ_OE/Higher CRSI) should be considered less vulnerable. Those counties in the lower right quadrant may be more vulnerable in the GOM region. This quadrant includes four Louisiana parishes with the lowest CRSI scores in the region: Orleans, Iberia, Terrebonne and Lafourche. These parishes also have higher Risk scores. Particular attention needs to be given to the Society domain for these counties, which negatively impacted CRSI scores in the lowest ranked counties for the region, in addition to lower scores in the other domains. All nine parishes in Louisiana had CRSI values lower than most other ocean economic dependent counties.Coastal counties share certain governance approaches, natural resource practices, built environment requirements, and demographic characteristics not shared with non-coastal counties. Thus, an analysis that includes all counties tends to “dilute” differences among coastal counties. To differentiate among coastal counties with ocean economies, a regional ENOW coastal county rescaled analysis specifies the differences in CRSI scores within the identified region. This rescale differentiates patterns among ENOW coastal counties and allows for a more relevant assessment of potential areas for improvement in coastal areas.While the original CRSI quantitative resilience scores are useful for comparisons across the nation, they may offer little to direct investment for the enhancement of overall resilience at regional and state levels . ApplicaResilience and sustainability are inextricably linked to economic conditions and activities . The LocAt a macroeconomic level, community resilience can be clearly influenced by economic sectors . Using eHigh ocean dependence (LQ_OC) and a lack of ocean sector diversity should be considered an indicator of added economic vulnerability along with the economic indicators already in the CRSI Society domain. For example, parishes in Lousiana with a dependence on Ship Boat Building (SBB) or the fishing industry, tend to have lower resilience scores. These two industries may exacerbate vulnerabilties not pinpointed specifically in CRSI scores. Hurricanes can completely close fisheries for extended periods of time and the impact of coastal flooding and hurricanes may exacerbate contamination exposures  associated with the SBB industry and other ocean sector industries in addition to directly impacting the economic vitality. It is not suggested that ENOW coastal counties in the GOM region are less resilient overall based on their dependence on the ocean economy, but they may be slower to recover in the event of hurricanes and coastal flooding because of this dependence. Futhermore, loss of employment in ocean economy sectors following natural hazard events could impact the well-being of those coastal communities.LQ and CRSI information may be used to look within each state to evaluate resilience differences by focusing on the commonality of ocean economic dependence. In Alabama, Baldwin County is two times more dependent on the ocean economy than Mobile County; however, Baldwin County scores much higher for resilience. The counties also have different industry profiles for the ocean economy sector employment. With similar risk profiles, domain scores need to be dissected to the indicator level to evaluate how these economic dependences may influence resilience. Measures such as the LQ could be linked back to a variety of socio-ecological measures used in the CRSI Society domain and is worthy of further examination.Examining the intersections among different domains and indices is an important aspect of improving SES resilience characterizations . BringinRegionally-derived resilience indices for GOM counties  have shoThe CRSI re-scaling approaches described in this paper can be transferred to other specific geographies and the data used to calculate CRSI and LQ values are both publicly available. Employment dependence as presented for LQ can be tailored to specific industries within the geographic area of interest. However, approaches to refine rescaled CRSI characterizations for geographically specific areas may be needed and could include a finer scale population-based exposure characterization of risk. Additionally, metrics for the Governance domain of CRSI could be further developed for specific geographic areas using regional or state level resilience plans not consistent enough for national comparisons. In coastal areas, the number of ecological restoration, structural protection, and/or non-structural risk reduction projects that are planned or being implemented may be appropriate to improve natural or built environmental domain measures. For example, Louisiana’s Comprehensive Master Plan for a Sustainable Coast  identifiAnother consideration for refining CRSI for regional applications may be a substitution of regional, more specific LQ values for the Hackman Index as the sole measure of economic diversity, and inclusion of the Gini coefficient as a metric of socio-economics. Lastly, the addition of regionalized quality of life measures to the CRSI/LQ typology would be useful for setting baselines to help communities look to one another for improving their most important quality of life aspects and to better track progress over time following extreme weather events and natural disasters. These combinations of measures and further refinements will strengthen U.S. coastal county resilience characterizations and may increase the likelihood of improving environmental, social and economic recovery outcomes.ENOW coastal counties share certain governance approaches, natural resource practices, built environment requirements, and demographic characteristics. These qualities support the need for resilience characterizations specific to coastal regions. Although national level assessments exist, re-scaling CRSI assessments to ENOW coastal counties within regions highlights resilience strength and weaknesses otherwise diluted in the national level assessments. In addition, combining the LQ as measure of employment dependence on ocean economies with CRSI scores captures a potential vulnerability specific to coastal counties which is not reflected in CRSI alone. Including regionalized quality of life indicators/indices to the CRSI/LQ typology could help strengthen resilience assessments as an additional measure of vulnerability of the people living and working in ENOW coastal counties. The information presented can help communities identify opportunities  to strengthen resilience and improve overall community well-being. The unique approach of combining CRSI and LQ for characterizing natural hazard resilience described could be transferred to other specific geographies as defined by population groups, hazard profiles and economic dependence.SI


During the course of the 2015–2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5–3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings. During the 2015–17 Zika outbreak in the Americas, many research sites struggled to rapidly establish cohorts to study the neurodevelopmental outcomes of exposed infants and children, due to both logistical difficulties and a lack of appropriately adapted/validated neurodevelopmental tools. During this time period, we conducted a study evaluating the neurodevelopmental outcomes of post-natal ZIKV and dengue virus (DENV) infection among of infants (<3 months at enrollment) and children (1.5–3.5 years at enrollment) at a site in rural, southwest Guatemala. The study, which enrolled a cohort of 500 mother-infant pairs and 400 children, was a collaborative effort that leveraged expertise at multiple institutions to rapidly implement a study protocol in a resource-limited region of Guatemala. In this Methods paper, we describe the study methodology, how we implemented our research protocol in this rural, resource-limited community, and challenges and lessons learned during its operationalization. Specifically, we address how we adapted neurodevelopmental testing tools to the local language and cultural context, trained and managed a research team recruited from the local community, maintained competency and quality control in this workforce, developed critical laboratory infrastructure, and engaged with local community stakeholders. Our approach may serve as a guide to other researchers carrying out future studies focusing on child neurodevelopment as well as clinical evaluation of ZIKV and other emerging infectious diseases of public health priority. In 2015, an outbreak of Zika virus (ZIKV) was reported in Brazil and other Latin American countries . Even inThe National Institute of Allergy and Infectious Diseases (NIAID), through the Vaccine and Treatment and Evaluation Unit (VTEU) network supported our proposal to assess the neurological and neurodevelopmental impact of postnatal ZIKV infection in infants and young children. The Center for Human Development (CHD) of the Fundación para la Salud Integral de los Guatemaltecos (FUNSALUD), which had an ongoing maternal-child health program, “Creciendo Sanos,” had ample experience with active surveillance for dengue virus (DENV) infections and was well positioned to carry out this study . The earThe first section of this manuscript describes the study methods and study procedures as described in the study protocol and manual of procedures. The second section describes the challenges and lessons learned from the rapid operationalization of a large prospective cohort study in response to the ZIKV epidemic in a rural, resource-limited setting in Guatemala. Our approach to overcoming real-life challenges encountered in a resource-constrained setting may serve as a guide to other researchers carrying out future studies of ZIKV and other emerging infectious diseases of public health priority. Results from the study described in this paper will be published in a future manuscript.The following section describes the study objectives, study population and study procedures as described in the study protocol and manual of procedures (MOP).The primary objective of this prospective natural history cohort study was to characterize the acute and post-acute clinical, neurological and neurodevelopmental outcomes of postnatally-acquired, laboratory-confirmed ZIKV infection in newborn infants and their mothers (infant-mother pairs), as well as older children ages 1.5–3.5 years old who may have been postnatally exposed to ZIKV during the 2015–2017 outbreak. The study also aimed to describe the clinical characteristics, viral load and kinetics of humoral immune responses during acute laboratory-confirmed ZIKV infection in infants and young children, including the potential for antibody-dependent enhancement (ADE) during acute ZIKV infection in those previously exposed to or with maternally-derived antibodies against DENV.2 area in the southwest Trifinio (SWT) region of Guatemala, a rural lowland area that borders Chiapas, Mexico and is hyperendemic for vector-borne infections [Children and mothers were enrolled from 22 communities, living within a 200 kmfections  A communfections . In 2013fections ,10Infant-mother pairs  were eligible if the child was 0–2.9 months of age, and the mother was ≥16 years of age. Informed consent was signed by the mother if ≥18 years old. If the mother was 16–17 years of age a grandparent signed the informed consent and the mother provided assent . Older children 1.5–3.5 years of age at enrollment were eligible if they either participated in a prior 2015–2016 dengue acute febrile illness (AFI) surveillance study (cohort A) or were a sibling of an infant enrolled in cohort B (cohort C), and consent for participation in this study was signed by one of the parents.The study was granted approval by the Institutional Review Boards (IRBs) of Baylor College of Medicine (BCM), University of Colorado (CU) Multiple IRB (COMIRB), and the Ministry of Public Health and Social Welfare (MSPAS) of Guatemala in May of 2017. All study participants provided guardian informed consent prior to initiating study activities.Infant-mother pairs were screened and enrolled from the CHD maternal and child health program and from referrals of pregnant women who were close to delivery or had delivered an infant in the previous two months by community health workers. Children 1.5–3.5 years of age who previously participated in the dengue AFI surveillance study were contacted for enrollment in this study.At baseline, we recorded demographic information, including each child’s date of birth, sex, birth weight (if available), gestational age (reported by mother), household location and household characteristics. We also documented medical history and information about initiation of breastfeeding and history of vaccinations. The child’s length, weight, and head circumference were measured using WHO’s recommended procedures .BaselineProtocol-required household visits at various intervals were conducted by trained study staff at the subjects’ homes or at the study clinic in order to collect health data and to perform anthropometric measurements, clinical and neurological exams, neurodevelopmental tests, and ophthalmologic and hearing evaluations. Blood, urine and breast milk samples were also collected during household visits (. Caregivers responded to a standardized questionnaire designed to document the presence of FLI and other Integrated Management of Childhood Illness (IMCI) danger signs [nd, 3rd or 4th week after the first visit to evaluate seroconversion. The timing of the second visit was selected at random for each study subject.Both ZIKV and DENV infections can be asymptomatic or subclinical in 70–80% of the infected population, or present as an acute illness with or without fever ,13. Therer signs . If a chTable 2). Through a process of team discussions and reflections based on our experience conducting the present study and multiple other studies in Guatemala and other LMICs, we identified overarching lessons learned and recommendations that may guide other researchers and clinicians conducting prospective multi-disciplinary studies in other low-resource settings in response to emerging infections  and study coordinators  held meetings after completing the enrollment phase to develop a comprehensive list of the most salient challenges faced during the study operationalization, which were summarized and iteratively reviewed by the study team until no other challenges were identified. For each of the challenges, we describe at least one solution that was implemented by our team. To accurately describe such solutions, the first author (AP) revised the manuals of procedures, minutes from team meetings held since the start of the study, administrative documents, and emails that documented key decisions on study operationalization made by the study team. We grouped challenges and solutions into the following categories: neurodevelopmental assessments, human resources, bioethical procedures, community engagement, data collection and quality control  and three new data managers, who were graduates from business administration or accounting due to the scarcity of trained data managers at the study site. Forty community health workers who were mothers recognized as leaders in the community, were financially compensated to serve as the bridge between study nurses and community members, helping to disseminate information about the study, identifying potential participants, sending study visits reminders, and communicating community concerns to the study team. All personnel, including community health workers, were trained in NIH human subjects protection (HSP), Good Clinical Practices (GCP) and principles of clinical research following the NIH regulatory training, the Special Programme for Research and Training in Tropical Diseases (TDR) Global Competency Framework for Clinical Research, and the WHO Ethics in epidemics, emergencies and disasters: Research, surveillance and patient care manual ,24.. Weekly and daily specific and measurable goals were established and monitored by each field coordinator to ensure that enrollment, retention and study procedures goals were met.The study manual of procedures (MOP) and various standard operation procedures (SOPs) were developed, reviewed and refined as needed during the study operationalization. Study coordinators developed checklists summarizing visits and key procedures  to train, supervise and provide feedback to the research staff on an ongoing basis. To ensure the implementation of multiple and complex procedures as required by the study protocol, we created competency-based sub-teams responsible for certain procedure clusters: recruitment and enrollment visits, symptomatic surveillance, FLI visits, and follow-up visits. Each sub-team included 2–6 study nurses and one field coordinator  on how to review research studies and advocate for their communities. Research nurses from the participating communities provided their local expertise and helped enhance the study buy-in. Local leaders, midwives and nurses identified and referred potential study participants and maintained communication with families enrolled in the study. Community collaborators were trained on the essentials of GCP and Human Subjects Protection by an anthropologist from CU.Communities in SWT are characterized by involving community leaders and families in decision making. For this reason, it was important to socialize the study informed consent to communities and families, before individuals’ consenting. Prior to initiating research activities, lead study staff obtained community buy-in by presenting and discussing the study aims, procedures, and potential risks and benefits with community leaders. A simple and culturally-appropriate visual informed consent tool (available on request) was used to explain the study objectives and procedures in Spanish  to potential participants, highlighting the differences between research and healthcare services to families with low literacy levels and limited or no previous exposure to medical research. Informed participants older than 18 years old provided informed consent prior to study procedures. If participating mothers were 16 to 17 years old, informed consent was obtained from one of their parents and assent was provided by the mother. If the participant providing consent was illiterate, a third party witnessed the consent process and signed the informed consent form, while the participant provided thumbprints. Our approach to community engagement and bioethical procedures facilitated the enrollment of 500 infants along with nearly 400 children 1.5–3.5 years of age with a high percentage of enrolled-to-screened participants and a low percentage of lost to follow-up participants. Results will be published in a future manuscript.Dissemination of final results  was planned in collaboration with the Community Advisory Board for Research (CABR), community leaders and local public health facilities.The study catchment area covered a large geographic zone, with deteriorated roads and limited transportation. For this reason, reducing participant mobilization and finding alternative sites, other than CHD clinic, to conduct study visits was needed. Visits were therefore conducted at multiple settings, including satellite clinics, a converted bus and participant’s homes. In order to collect large amounts of data in a location with limited access to internet, an electronic, smartphone-based CommCare app  was developed. Study staff collected data online or offline and uploaded it to an electronic server in real-time or as soon as internet was available, at least once daily. Research nurses completed most questionnaires , while trained psychologists and physicians documented neurodevelopmental and medical evaluations into paper-based source documents and later entered in the CommCare mobile application. In addition, information related to clinical visits and hospitalizations since the previous study visit was collected and entered into a secure local electronic REDCap database  if participants consented.To ensure adherence to GCP standards, a quality control plan was developed with a priority list of indicators for quality assurance. The quality control coordinator reviewed all the informed consent forms and 10–20% of the individual study records, conducting a comparison audit of the paper-based forms and the electronic databases. We aimed for 100% compliance with informed consent indicators. As data were entered in real-time, all completed data collection forms were reviewed daily by study coordinators. In addition, The Emmes Company, LLC, a data management group, updated online process quality reports daily or weekly allowing local data managers to address data issues  on an ongoing basis. Site specific report logs were maintained in a secure file sharing Website that provided real-time, site-specific feedback to identify errors and/or omissions in data entry and to facilitate corrections with minimal time delay.Study coordinators conducted staff refresher trainings every two months as well as monthly field supervision of study staff procedures and data collection, while study investigators conducted random spot-checks of field work and home visits. Feedback through on-the-spot discussion of supervisors’ findings, weekly staff meetings, and monthly written reports to all staff and external collaborators was done with the aim of ensuring high quality performance of study procedures.During weekly meetings, study progress, challenges and solutions were discussed among leaders from the field team, CU, Baylor University, Emmes, and NIH representatives. In addition, principal investigators conducted monthly on-site supervisions. Given the high ambient temperature (25–38°C), long transit times and harsh environment at SWT, a strict protocol for ensuring quality collection of samples and maintaining cold chain in the field was developed, allowing for 95% of samples to meet with temperature requirements. Whole blood was collected in EDTA tubes for ZIKV and DENV serologic and molecular testing and processed to obtain plasma for ZIKV serologic and molecular testing, and other congenital infections. Saliva was collected using a CultureSwab Collection and Transport System by brushing the participants’ cheek and soaking it with saliva for at least 20 seconds, and the sample was then mixed with 200 uL of Invitrogen  nucleic acid stabilizer buffer. Urine and breast milk samples for ZIKV molecular testing were collected in sterile containers. All samples were transported in temperature-controlled portable coolers and delivered to the study laboratory for storage at 2–8°C until processing. Samples were stored at -80°C from processing until international shipment. Retained blood samples included whole blood and plasma aliquots. Samples were shipped periodically to the NIH sample repository  preserving the cold chain and following international guidelines for shipping biologic materials. Specimen analyses included IgM, IgM, neutralizing antibodies and PCR.Trained research nurses collected blood, saliva, urine and breast milk samples at the participants’ households or at the satellite clinics per study protocol  research laboratory and 1500 sqf research operations area for personnel, data management, secure document storage and meetings, with the support of the CU Strategic Initiative for Research. While the CHD has a connection to the power grid and a high-capacity generator, the stability of energy supply was reinforced by two additional generators to safeguard samples stored at the laboratory. During the conduct of this study, a solar-based energy system was installed. The laboratory had the capacity to process and store approximately 10,000 samples or aliquots, stored at -20°C or -80°C.We described the rapid, intensive, and successful operationalization of a unique population-based prospective cohort study in a low-resource setting in rural Guatemala during the emergence of ZIKV in the Americas.Our team faced multiple challenges due to the fast-paced nature of our work, large amounts of complex study procedures, and a study setting in a large geographic region, with high poverty rates, low literacy levels, and limited access to healthcare. Most importantly, we dealt with the very limited research infrastructure and resources that characterizes countries like Guatemala, and especially rural regions like SWT, where this study was conducted . DespitePopulation-based studies with well-defined denominators, like our study, have the ability to provide incidence rates of emerging infectious diseases, their consequences and other relevant outcomes in low-resource settings. For example, this study can provide information on the incidence of microcephaly and neurodevelopmental outcomes, which are increasingly being documented in low-resource settings ,27. In aAs an example of developing culturally-appropriate study procedures, the neurodevelopmental assessments were selected from standardized measures in high-income countries, translated to Spanish and adapted to the local culture. Verbal administration of neurodevelopmental questionnaires and visual aids for Likert scales facilitated parental understanding of questions and addressed the local limited literacy levels. The inclusivity and adaptation of the informed consent process to ensure community engagement and participation allowed us to meet GCP and bioethics standards . DevelopAssembling a highly trained and committed group of local researchers under the mentorship of experienced investigators is key to rapidly operationalize and sustain a study of this magnitude in the context of multiple local challenging conditions. Developing clear SOPs, forming sub-teams with specific roles, conducting well-planned trainings with frequent refreshers, performing on-site supervision and real-time feedback, and establishing strong team motivation for continuing education and career development are paramount to maintaining data quality and meeting study recruitment goals.Population-health studies provide a unique opportunity to build local capacity and empower local investigators. Our study has provided many young nurses, who gained experience from well-structured ethical and research procedures trainings, with professional growth and special expertise that can help them contribute to enhancing local and regional clinical and public health practice. Many of our study supervisors have now advanced their careers by pursuing additional studies and degrees in epidemiology and public health, and they have grown to serve as study coordinators, laboratory managers, and data management coordinators, providing a positive circle of growth in which they serve as role models for young people and potentially become future leaders in their communities.


Who smokes, and why do they do it? What factors discourage and otherwise reward or incentivize smoking? Tobacco use has been accompanied by controversy from the moment of its entry into European culture, and conflicting opinions regarding its potentially adverse influence on health have coexisted for hundreds of years. Its use in all forms represents the world’s single greatest cause of preventable disease and death. Tobacco was introduced to Europe by Christopher Columbus, who in October 1492 discovered the crop in Cuba. While the next four centuries would see tobacco as the most highly traded economic commodity, by 1900, the now familiar cigarette remained obscure and accounted for only 2% of total tobacco sales. Global tobacco consumption rose sharply after 1914 and became especially prevalent following World War II, particularly among men. Indeed, overall tobacco sales increased by more than 60% by the mid-20th century, and cigarettes were a critical driver of this growth. Cigarettes dominated the tobacco market by 1950, by then accounting for more than 80% of all tobacco purchases. In the absence of clinical and scientific evidence against tobacco, moral and religious arguments dominated opposition voices against tobacco consumption in the 1800s. However, by the mid-20th century, advancements in medical research supported enhanced government and voluntary actions against tobacco advertising and also raised awareness of the dangers associated with passive tobacco smoke exposure. Solid epidemiological work connecting tobacco use with “the shortening of life span” began to appear in the medical literature in the 1950s, linking smoking with lung cancer and related conditions. In subsequent years, these developments led to significant curtailment of tobacco use. This monograph explores aspects of the intersection of tobacco with themes of behavioral incentives, religion, culture, literature, economics, and government over the past five centuries.


The physical environment is of critical importance to child development. Understanding how exposure to physical environmental domains such as greenspace, urbanicity, air pollution or noise affects aggressive behaviours in typical and neurodiverse children is of particular importance given the significant long-term impact of those problems. In this narrative review, we investigated the evidence for domains of the physical environment that may ameliorate or contribute to the display of aggressive behaviours. We have considered a broad range of study designs that include typically developing and neurodiverse children and young people aged 0–18 years. We used the GRADE system to appraise the evidence. Searches were performed in eight databases in July 2020 and updated in June 2022. Additional articles were further identified by hand-searching reference lists of included papers. The protocol for the review was preregistered with PROSPERO. Results: We retrieved 7174 studies of which 67 are included in this review. The studies reported on green space, environmental noise and music, air pollution, meteorological effects, spatial density, urban or rural setting, and interior home elements . They all used well validated parent and child reported measures of aggressive behaviour. Most of the studies were rated as having low or unclear risk of bias. As expected, noise, air pollution, urbanicity, spatial density, colour and humidity appeared to increase the display of aggressive behaviours. There was a dearth of studies on the role of the physical environment in neurodiverse children. The studies were heterogeneous and measured a range of aggressive behaviours from symptoms to full syndromes. Greenspace exposure was the most common domain studied but certainty of evidence for the association between environmental exposures and aggression problems in the child or young person was low across all domains. We found a large knowledge gap in the literature concerning neurodiverse children, which suggests that future studies should focus on these children, who are also more likely to experience adverse early life experiences including living in more deprived environments as well as being highly vulnerable to the onset of mental ill health. Such research should also aim to dis-aggregate the underlying aetiological mechanisms for environmental influences on aggression, the results of which may point to pathways for public health interventions and policy development to address inequities that can be relevant to ill health in neurodiverse young people. The physical environment encompasses all aspects of a child’s physical world and may be defined as objective characteristics of the physical context in which children spend their time . The influence of children’s physical exposures has been summarised differentially by various models, theorems, and theorists over the previous century. Notably, these include the physical environmental elements of children’s exposome , restoration  and instoration, whereby attributes of the physical environment, such as greenness in particular, may promote physical activity and social capital and cohesion ,9,10.Previous theories have primarily focused on the stress-reducing effects of greenspace, either via a protective influence from harmful environmental stimuli (noise and air pollution) ,12,13, oThe literature also indicates that aspects such as ambient air particulate matter exposure may negatively impact development via neuroinflammatory pathways ,22,23,24As discussed, social-behavioural mechanisms may explain the relationship between aggression and climate effects, for example the routine activity theory proposes that warmer temperatures facilitate more frequent social interaction, increasing opportunity for aggression . AlternaFrom the evidence presented so far, it appears that both physical and social environments, in addition to genetic and epigenetic influences, shape the developmental trajectories of children ,44,45,46Externalising disorders are characterised by display of a range of behaviours which are associated with poor impulse-control, and include rule breaking, impulsivity, and inattention; in addition, a core component of these conditions is the presence of heightened aggression. Specific child and adolescent externalising disorders include conduct disorder (CD), oppositional defiant disorder (ODD), and attention- deficit-hyperactivity disorder (ADHD). Of particular concern is this repeated presence of aggressive behaviour in these disorders as it is often associated with referral to services and application of a range of restrictive practices, most commonly antipsychotic medications but also inpatient admissions. Aggressive behaviours and general behavioural problems such as destructive behaviours have an overall negative influence on carers due to stress and negative interactions between carers and the person they care for, likely resulting in a deterioration of the quality of care . MoreoveThese behaviours in both typically developing and neurodiverse children compound societal and educational limitations ,59,60,61Neurodevelopmental disorders (NDDs) are a category of “etiologically diverse conditions” with onset during the developmental period and are characterised by below average intellectual functioning and adaptive behaviour . This clAbout one in one hundred individuals has a neurodevelopmental disorder and there are about 351,000 children with intellectual disability in the UK, often coexisting with other neurodevelopmental disorders . PrevaleWhilst previous research has examined predictors of broadly defined challenging behaviour in children with intellectual disability ,87,88, nTherefore, in this narrative review, we examine the certainty of evidence of the impact of the physical environment on typically developing and neurodiverse children’s aggressive behaviours. The outcome of interest was either psychological or biological proxies of aggressive behaviour, annoyance and irritability measured by validated psychometric questionnaires  or biological markers such as blood pressure, heart rate and skin conductance. The findings are presented by environmental domain  and separately for typically developing and neurodiverse children.We adhered to the Preferred Reporting Items of Systematic reviews and Meta-analyses (PRISMA) statement checklist  in conduThe electronic search strategy comprised 8 bibliographic databases  and two grey literature sources (NICE evidence search and Google scholar). The inclusion of the latter sources facilitated the retrieval of additional studies from a more diverse range of sources , whilst mitigating publication bias and increasing the comprehensiveness of the review ,93. The Studies were included if they (a) reported primary research, (b) were written in English, French, German, Mandarin Chinese and Spanish which were languages spoken by fellow researchers and therefore could be translated, (c) included human participants aged between 0–18 years, (d) contained a psychometrically valid parent or child reported outcome measure of aggressive behaviours or physiological measures of arousal (identified as a proxy measure of aggressive behaviour) and (e) examined exposure to domains of the physical environment.All retrieved articles were screened by the first author (A.B.). A sub-sample of titles and abstracts (10%) were co-screened by a senior researcher (A.H.) and a post-doctoral researcher (R.R.). Inter-rater reliability for this initial screening was 87% (0.868). Full text data extraction was conducted by the main author (A.B.) using a modified flexible data extraction template used for non-Cochrane reviews  with co-Evaluation of the quality and validity of the exposure: whether the paper used established or validated environment metrics.Bias due to confounding: whether studies included adjustment for potential confounding variables.Bias due to sampling methodology and reporting of attrition rate.Outcome assessment leading to information bias: whether studies were using validated aggressive behavioural outcome measure(s).Risk of bias assessment (RoB) and GRADE protocol were adapted from a systematic review by Clark, Crumpler, and Notley  on the eOne measure of RoB that was not included in this review was “due to blinding to exposure outcome” as it was not considered appropriate for the methodology of the majority of the retrieved studies which infrequently blind outcome assessors. Overall RoB ratings for each study were aggregates of high, low or unclear across the four domains. We adopted a conservative rating strategy where studies that had equal reports of low and high risk of bias were classified as high.The GRADE system  is a widnormalised difference vegetation index (NDVI)) and percentage of neighbourhood greenspace.Greenspace was measured by land use data percentage of natural space in the neighbourhood  or measured within a set distance of the child’s residence. Other indices included satellite derived neighbourhood greenspace , and elemental carbon attributed to traffic (ECAT).Meteorological variables included seasons, hot or cold weather, humidity and sunlight.Spatial density and interior home/facility design included space per child in square metres (high/low density), wall paint, sensory room, presence of damp.Urbanicity and rurality were described by the location of the child’s residence or school.Strengths and Difficulties Questionnaire (SDQ) Age-appropriate Behaviour Assessment System for Children, Second Edition (BASC-2) Child Behaviour Checklist (CBCL) Health Related Quality of Life in Children (KINDL-R) ,102WHO Global School-based Student Health Survey National Institute of Mental Health Diagnostic Interview Schedule for Children 4th version (NIMH DISC-IV) State-Trait Anger Expression Inventory-2 (STAXI-2) Other outcomes used were observer rated frequency of aggressive behaviourThe studies utilised a number of psychometrically valid parent and child reported measures of aggressive behaviour, as well as observer ratings. These comprised the full instrument or conduct, aggression, and externalising behaviour domains as follows:The two searches retrieved 7434 records. After deduplication, 7174 were screened of which 257 underwent full-text assessment, resulting in the inclusion of 67 papers  examined associations between greenspace exposure and childhood aggression ,121,122.Inconsistent evidence for harms or benefits was reported across eight studies ,117,121 n = 23,665) assessed the association between environmental noise pollution including road traffic, construction noise, aircraft noise and aggression outcomes [Three longitudinal and eight cross-sectional studies  assessed the association of music on childhood aggression [Two studies  from the USA  explored the influence of air particulate matter on aggressive behavioural outcomes in typically developing children and young people [Eight longitudinal and six cross-sectional studies from Lithuania, China, Korea, Iran, Canada, USE, and the UK , and child self-reported conduct problems ,149. No Five longitudinal and two cross-sectional studies (approximately = 6314) from Chile, Canada, the Netherlands, USA, and Italy, assessed associations between meteorological variables and child aggression outcomes ,158,159.The study by Muñoz-Reyes et al.  contrastn = 8568) from the USA and the UK examined spatial density and architectural design in relation to childhood aggression. RoB was judged as high in all studies except one rated as unclear [Four observational and two longitudinal studies ,163,165  unclear . A study unclear ,161,162. unclear ,163 repon = 8257) conducted in Iran, the UK, and the USA examined the associations between interior design features and childhood aggression [Three studies, two quasi-experimental and one longitudinal  from the USA, the Netherlands, and Thailand explored the influence of urbanicity and rurality of residence on children’s aggressive behavioural outcomes [Three longitudinal and three cross-sectional studies  from the USA, Pakistan, the UK, and Australia included neurodiverse participants exclusively [Six studies . Another study [Baird et al.  exploreder study  reporteder study  examineder study  provideder study  assessiner study  examinedThis is the first narrative review that updates previous literature across several environmental domains as well as including neurodiverse children, a previously under reported population in other reviews.We found evidence that supports the therapeutic benefits of increased natural land and greenness surrounding child residences. Previous reviews have also shown associations between greenspace exposure and reductions in violent behaviours ,195. The greenspace evidence synthesised primarily supports the therapeutic influence of neighbourhood nature exposure on child aggressive behavioural outcomes. These effects, at least partially, were also present in NDDs populations. Whilst more epidemiological and experimental research paradigms are required to solidify the evidence for this therapeutic relationship and understand its underlying mechanistic pathways, we provide initial evidence for the role of nature in reducing aggression in neurotypical and diverse children. Initial attempts at establishing guidelines for integration and therapeutic adoption are beginning to be developed . StudiesChildren appear to consistently self-report higher aggressive and annoyance related behaviours related to environmental noise, whereas parent reported outcomes either show a lack of association or inconsistent associations both for harm and benefit. This may suggest that noise exposure operates on pathways involving subjective annoyance and irritation which may not translate into objective longer-term increases in aggression problems. Additionally, although noise annoyance may not play a direct role in the aetiology of those problems, noise exposure of individuals who experience frustration or irritable mood has been shown to increase its severity ,26. Nois2 exposure and childhood aggression problems. Tobacco smoke exposure showed a harmful association with aggressive behavioural outcomes irrespective of who was the outcome assessor. We also found this harmful association for childhood exposure to ambient air lead exposure (PbA). The lack of association of PM2.5 and PM10 with these behaviours is potentially anomalous when considering research that has linked air pollution with increased risk of mental health disorders [We found absent and inconsistent associations between ECAT, particulate matter less than PM2.5, particulate matter less than PM10 and NOisorders . The harisorders ,22,23,24Whilst none of the retrieved articles examined the effects of air pollution on neurodiverse children, it was shown that families of these children disproportionately reside in areas of higher particulate concentration than those of typically developing children , as wellSummer seasonality, humidity, temperature, and previous tornado exposure were consistently correlated with increased childhood aggressive behaviours. We found little evidence for either harmful or beneficial effects of ambient temperature and seasonality. Previous studies suggest that humidity compounds the negative effects of heat on mental health , as wellThe negative impact of high spatial density on aggression in young people  and inpaDue to the quality of retrieved evidence, we were unable to extricate any definitive conclusions for associations between urban or rural residence and childhood aggressive behaviours. This is potentially anomalous considering that children residing in rural areas are exposed to more greenspace which generally appears to have calming effects ,213,214.Previous work has associated damp problems with increased toxic mould, contributing to poor air quality  and/or pWhilst preliminary evidence from this review supported the positive impact of modified sensory rooms to de-escalate aggression, it is very limited in scope. One study  suggesteWe found preliminary evidence for the therapeutic potential of music in neurodiverse children which is similar with findings reported in adults . Music lThis review is comprehensive and has examined the evidence of a wide range of environmental exposures in relation to the display of aggressive behaviours in typical and neurodiverse children. To the best of our knowledge, this is the first review that comparatively examines available research on environmental determinants of aggression in these two groups. The review shows clearly the disproportionately sparse literature relating those children and the physical environment despite the fact that they are more likely to be affected by social adversity, poor housing, air pollutants, and poverty ,220,221.The incorporation of GRADE to assess the quality of evidence in this review may well be simultaneously both a strength and a limitation. Whilst it facilitated the examination of the certainty of included evidence, the adaptation of GRADE for use in a non-meta-analytic review including epidemiological studies, may, as highlighted previously , inadverA final limitation of this evidence synthesis is the inclusion of studies that adopt a diverse range of heterogenous physical environmental exposures and metrics. As has been highlighted previously by experts in physical environmental epidemiological analysis on child socio-cognitive outcomes , furtherPhysical environmental exposures sit at the intersection of social, biochemical, and (epi)genetic aetiological influences on the development and progression of a spectrum of physical and mental health outcomes. Further research can support stakeholders, ranging from city planners and environmental legislators to politicians and clinicians, in considering the role of the physical environment in the context of adverse impact on child (neuro)development. Whilst there is obvious need to further examine environmental and climate influences on mental health of all children, particular attention must be paid to neurodiverse children and their families. A recent report recommended that in order to pursue and achieve health parity for those children, we must “reduce poverty and improve living environments” . Researc


Restrained eating behavior has become the norm in college students' lives, and considering the harm it causes to college students, it is necessary to explore the factors associated with it. The aim of this study was to explore the association between media internalized pressure, body esteem, social physique anxiety, and restrained eating behavior.The participants in this study were 1,032 Chinese college students  and had a mean age of 20.22 years (SD = 1.277). They completed the Sociocultural Attitudes Toward Appearance Questionnaire-3, Body Esteem Scale (BES), Social Physique Anxiety Scale (SPAS), and Dutch Eating Behavior Questionnaire (DEBQ).The results showed that media internalized pressure was significantly and positively associated with college students' restrained eating behavior, that body esteem and social physique anxiety played a mediating role between media internalized pressure and restrained eating behavior, respectively, and that body esteem and social physique anxiety can also play a chained mediating role.This study reveals the relationship between media internalized pressure and restrained eating behavior, and the important role played by body esteem and social physique anxiety. Future interventions targeting restrained eating should focus on the aspects of body esteem and social physique anxiety. Restrained eating behavior refers to individuals restricting their food intake for weight loss  media internalized pressure is positively associated with college students' restrained eating behavior; (2) the higher the media internalized pressure, the more likely college students are to have lower body esteem and these students' restrained eating behavior will be more frequent, i.e., body esteem plays a mediating role between media internalized pressure and restricted eating behavior; (3) when college students experience greater media internalized pressure, the higher the social physique anxiety they feel and the more frequently restrained eating behavior they experience, i.e., social physique anxiety plays a mediating role between media internalized pressure and restrained eating behavior; and (4) the greater the media internalized pressure on college students, the more likely they may feel lower body esteem and likely to experience higher social physique anxiety, which makes them more likely to engage in restrained eating behavior, i.e., body esteem and social physique anxiety play chained mediating roles between media internalized pressure and restrained eating behavior. The conceptual model is presented in www.wjx.cn), which is a software that provides online questionnaire assessment services. We recruited participants in several ways as follows: (1) sent the link of the questionnaire to the class teachers via the Internet, who in turn distributed it to their students and (2) recruited participants by posting advertisements on social networks. A total of 1,244 college students participated in the questionnaire, and data from 1,032 participants were eventually included in the data analysis. The survey was anonymous and participants could withdraw from the survey at any time. A total of 212 participants' questionnaires were eliminated, mainly based on invalid responses, such as contradictory responses, and excessive consecutive identical or regular responses. Our study was approved by the Ethics Committee of the School of Public Health at Cheeloo College of Medicine of Shandong University (20190912), and all participants who participated in the survey gave informed consent to the study.The participants were all Chinese college students in this study. We collected data from seven universities . We distributed the questionnaires through the Questionnaire Star platform  was designed by Franzoi and Shields . This scThe Social Physique Anxiety Scale (SPAS) was designed by Hart et al. , and we The restrained eating subscale of the Dutch Eating Behavior Questionnaire (DEBQ) developed by Van Strien et al.  was usedThe SPSS version 24.0 software and its macro program PROCESS version 3.3 Hayes,  were usep < 0.001). Through the principal component analysis, we extracted a total of nine components with eigenvalues >1. It was found that 24.95% of the variance was explained for the first factor, which was lower than the required standard of 40%. This proves that the questionnaire used in this study has no common method bias , with an age range of 18–27 years. The final sample contained 439 (42.54%) male students and 593 (57.46%) female students. We performed the regression analysis after standardizing the variables. The bias-corrected percentile Bootstrap method was used to test all the above-mediated paths, and the selected Bootstrap self-sampling size was 2,000, with 95% CIs calculated. Findings from the mediation analysis are shown in This study investigated the association between media internalized pressure and restrained eating behavior, and the multiple mediating roles of body esteem and social physique anxiety in the relationship between media internalized pressure and restrained eating behavior among college students. We found that (1) there was a significant and positive association between media internalized pressure and restrained eating behavior; (2) body esteem mediated the effect of media internalized pressure on restricted eating behavior; (3) social physique anxiety mediated the effect of media internalized pressure on restricted eating behavior; and (4) body esteem and social physique anxiety play chained mediating roles between media internalized pressure and restrained eating behavior.Our study found that media internalized pressure was positively related to restrained eating behavior in our college student sample. Similar to our previous studies, Chang et al.  showed tWe found that media internalized pressure can relate to restrained eating behavior through body esteem and social physique anxiety, respectively, which supports our hypotheses 2 and 3. According to the cognitive behavioral model of eating disorders, the thin-ideal body shape promoted by the media increases individuals' misperceptions of their bodies during self-evaluation, which may cause low body esteem and anxiety, and even lead individuals to adopt unhealthy eating behaviors, such as restrained eating behavior . Finally, this study adopted an online method of distributing questionnaires; the measurement environment cannot be guaranteed to be consistent and, therefore, may introduce bias. Future studies may consider distributing and collecting questionnaires on-site.This study confirms the relationship between media internalized pressure, body esteem, social physique anxiety, and restrained eating behavior. There is a significant and positive association between media internalized pressure and restrained eating behavior among college students. Moreover, media internalized pressure can also increase the risk of restrained eating behavior through the parallel mediating effects of body esteem and social physique anxiety, as well as through the sequential mediating effects of body esteem and social physique anxiety.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethics Committee of the School of Public Health at Cheeloo College of Medicine of Shandong University (20190912). The patients/participants provided their written informed consent to participate in this study.TF and SX completed the writing of the introduction and discussion. JY completed the writing of the methods. TF completed the writing of results, data coding, cleaning, and the first draft of the manuscript. JW and GS completed the writing review and editing. All authors contributed to the article and approved the submitted version.This research was supported by the Social Science Fund of Shandong Province, China (No. 18DTYJ02), the Teaching Research Project of Shandong University (No. XYJG2020025), and the Young Scholars Program of Shandong University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patellar resurfacing (PR) and peripheral patellar denervation (PD) are common surgical treatments for knee osteoarthritis (KOA) in total knee arthroplasty (TKA). The aim of study was to compare preventive effect on postoperative anterior knee pain (AKP) between PR and peripheral PD in TKA. A total of 202 patients who underwent unilateral TKA were randomized into 3 groups: T, TPD, and TPR. Patients in T group received simple TKA, patients in TPD group received TKA combined PD while patients in TPR group received TKA combined PR. Incidence, intensity, and presentation time of AKP and clinical outcomes were evaluated at 3, 6, 9, 12, 18, and 24 months postoperatively. The incidence of AKP was significantly lower and the intensity of AKP and patients’ satisfaction score were significantly better at 3 months after surgery in group TPD and TPR compared with group T. Compared with group TPR, the intensity of AKP was significantly better at 3 months after surgery in group TPD. There were no significant difference in Oxford knee score, range of motion (ROM), patellar score, knee society score (KSS) and activities of daily living (ADL) score among 3 groups in the follow-up period. Both PD and PR can effectively reduce the intensity and incidence of AKP after TKA and improve patients’ satisfaction at 3 months after TKA. Additionally, PD is more effective on alleviating AKP than PR. KOA is a degenerative disease in the middle-aged and elderly, which is caused by cartilage degeneration, fibrosis, wear and tear, subchondral bone sclerosis, cystic change, osteophyte formation at the edge of the joint, synovitis hyperplasia, and then leads to joint capsule and ligament contracture. As KOA developed, the pain of knee joint is obvious and the activity is seriously limited. X-ray shows multiple osteophyte hyperplasia in the joint, and the gap is narrow or even disappears. Severe cases may be accompanied by varus or valgus deformity. End-stage KOA seriously affects the health and quality of life of middle-aged and elderly people, causing a huge economic burden to patients and society.,4 Compared with traditional conservative treatment, knee arthroplasty has become one of the important means to solve end-stage KOA, especially total knee arthroplasty (TKA). TKA can relieve patients’ joint pain and dysfunction to the greatest extent, and restore joint function.,6With the increasing trend of population aging, more and more elderly people are troubled by knee osteoarthritis (KOA). However, a retrospective study of 15 years after TKA showed that 20% of patients were dissatisfied with TKA, and one of the main reasons was the occurrence of anterior knee pain (AKP). In TKA operation, the injury of soft tissue around patella, such as ligament, synovium and infrapatellar fat pad, is the cause of AKP. Intraoperative nerve compression and traction are also related to the occurrence of AKP. AKP after TKA will seriously affect patients’ daily activities , especially for Asians who are used to sitting cross legged.,10 Therefore, it is urgent to explore effective solutions to AKP after TKA.In light of the maturation of TKA and prosthetic design technologies, more and more people choose TKA to treat end-stage KOA. Zhou et al have confirmed that the annual average growth rate of TKA surgery volume in China from 2009 to 2015 was more than 20%. and peripheral patellar denervation (PD). Thiengwittayaporn S et al have confirmed that peripheral PD  can effectively reduce the incidence of AKP after TKA and improve the activity function of the knee joint. Chen K et al conducted a meta-analysis including Thirty-two trials and 6887 knees to compare the outcomes of PR and nonresurfacing in TKA. The results showed that PR could reduce the occurrence of reoperation and noise after surgery, as well as increase the knee society score (KSS) and function score, while it might not influence the outcomes such as AKP, ROM, Oxford score, KOOS, visual analogous scale (VAS), Feller score, patellar tilt and the patients’ satisfaction. Therefore, TKA combined with PR and peripheral PD are effective interventions to reduce AKP after TKA. However, there is still no research to compare the above 2 preventive measures of AKP.For APK after TKA, many clinicians and medical scientists have made many preventive explorations in animal models and clinical practice, including patellar resurfacing (PR)Given that, the aim of this study was to compare preventive effect on postoperative AKP between PR and simple peripheral PD in TKA, so as to provide a theoretical basis for making a more comprehensive treatment strategy for patients with KOA.This prospective, randomized, controlled study was designed in accordance with the principles outlined in the Declaration of Helsinki. This study has been approved by the institutional review board of the Third Hospital of Hebei Medical University and all participants have signed informed consent forms.From July 2017 and January 2020, patients underwent unilateral TKA in the Third Hospital of Hebei Medical University were enrolled. The inclusion criteria were as follows: Osteoarthritis, the diagnosis meets the diagnostic criteria of osteoarthritis determined by the American rheumatology society, and it is ineffective after conservative treatment; The pathological degree of the knee joint on the operative side was basically the same, and both reached a severe degree; The clinical and imaging data of participants were complete; Preoperative American Society of Anesthesiologists physical classification: Ⅰ to Ⅲ. The exclusion criteria were as follows: History of infectious arthritis and osteomyelitis; History of patellar fracture or patellofemoral joint surgery; Have a history of tibial osteotomy, artificial hip replacement or patella fracture; Lower limb deformity and restricted movement caused by other reasons; Patients with cerebral infarction, Parkinson’s disease, Alzheimer’s disease, psychosis, etc, which affect postoperative rehabilitation exercise and follow-up compliance; Range of motion (ROM) are less than 90° or flexion contracture are more than 30°. Then patients were randomly assigned into 3 groups with random number table: TKA group (group T), TKA combined with PR (group TPR) and TKA combined with PD (group TPD).With the PS total knee system , all procedures were carried out utilizing a minimally invasive method. Every patient underwent standard intraoperative monitoring, such as oxygen saturation, electrocardiogram, and noninvasive blood pressure measurements and was given general anesthesia during the procedure. Patients were given propofol, midazolam, and fentanyl/sufentanil to complete anesthesia induction and received laryngeal mask placement and mechanical ventilation. Controlling BIS 40 to 60 allowed for the preservation of anesthetic depth. Palonosetron (0.25 mg) were administered to combat postoperative nausea and vomiting.All TKAs were done using an anterior midline longitudinal skin incision and a medial parapatellar arthrotomy. The front of the patella is cut through after the incision is made on the proximal side of the kneecap. As for the medial edge of the tibial nodule, the skin, subcutaneous and fascia are cut in turn, along the midline of the quadriceps tendon to the superior, and then along the medial side of the tibial nodule along the medial edge of the patellar ligament. The knee cavity can be seen by opening the patella. The knee was bent at 90 degrees and the joint capsule was stripped, thereby extensively exposing the interior of the knee. The joint cavity was cleaned, the medial-lateral meniscus, proliferating osteophytes, anterior cruciate ligament, and partial subpatellar fat pads were removed, and the soft tissue around the knee. All prostheses were used with no retained posterior ACL type. For TKA, the technique utilizing intramedullary femoral and extramedullary tibial alignment guides was followed. Choose the proper prosthesis when the osteotomy is finished. The knee was bent to 90 degrees without dislocating after all knee prosthetics had been fixed in place. the cement was fixed, the knee was bent and extended again, and the knee alignment, lateral collateral ligament tension and the patella movement trajectory were checked. Patients in group TPR received additional PR: Following the measurement and recording of the patellar thickness, the osteotomy thickness was calculated. Symmetrical osteotomy was performed with a patellar guide, requiring the reserved patellar thickness of at least 12 mm after the osteotomy. The patella prosthesis was installed and the patella thickness was measured again, requiring the displaced patella to return to its original thickness  score, patient satisfaction score, and VAS of overall knee pain was performed by another clinician blinded to the trial intervention. A goniometer was used to measure the active knee flexion and extension angles of the patient while supine. Three months postoperative radiographic parameters were evaluated by 2 independent investigators who were blinded to trial interventions using a picture archive and communication platform. Radiographs taken anteroposteriorly were used to measure the tibiofemoral angle. Congruency of the patella was assessed using Merchant view and measured by lateral patellar tilt, displacement of the patella from the midline of the trochlea patellar displacement and patellar shift index. We hypothesized that the incidence of AKP would decrease from 20% to 10% after TKA combined with PR or PD. A minimum sample size of 60 subjects per group or 180 subjects overall was required with a significance of 0.05 and a strength of 0.9 (PASS 15.1). Based on a 10% abscission rate, the sample size was 66.After simple TKA, approximately 20% of patients developed AKP.t test (Student t test) and chi-squared test. An independent t test and the chi-squared test were used to compare clinical and radiographic outcomes between 3 groups. A P value of .05 indicates a statistical difference.All statistical analysis was performed with the Statistical Package for Social Sciences software . The continuous data were expressed as mean ± standard deviation (SD) or median . The demographics and preoperative data of 3 groups were compared using the independent In total, 222 eligible patients were enrolled from July 1, 2018 to December 31, 2021. Among them, 12 patients did not meet the inclusion criteria, 8 patients refused to participate this study. Finally, 202 patients were randomly assigned into 3 groups: TKA group , TKA combined with PR group  and TKA combined with peripheral PD group   and the intensity of AKP was significantly better at 3 months after surgery  but not at the later follow-up time points in group TPR and TPD. Compared with group TPR, the intensity of AKP was significantly better at 3 months after surgery in group TPD  and there was no difference in the incidence of AKP between 2 groups  and VAS score was significantly lower  at 3 months postoperatively but not at the later follow-up time points in group TPR and TPD  and Duan et al (including 37 studies and 1641 patients with AKP) showed that peripheral PD could effectively reduce the incidence of AKP and VAS score within 12 months after surgery. In this study, we found that compared with conventional TKA, the incidence of postoperative AKP, the degree of AKP and VAS score in patients receiving PD 3 months after TKA were significantly reduced, and the patient satisfaction was significantly improved, while the knee function remained unchanged after operation, which was consistent with the results of Thiengwittayaporn et al:The purpose of PD is to block nerve innervations to the vastus medialis and the vastus lateralis in order to reduce AKP after TKA. Although the effect of this method to reducing forward anterior knee pain after TKA has been controversial, the mid-term effect is definitely.Based on the above advantages of PR and Pd on APK after TKA, we further compared PR and PD. The results showed that the intensity of AKP was significantly better at 3 months after TKA in group TPD, while there was no significant difference in other indicators. The reason may be that the aseptic loosening and subluxation of the inserted patellar prosthesis increase the degree of AKP.It is undeniable that there are still some limitations in the present study. Firstly, the single center and prospective analysis design leads to some selection bias of the data; secondly, due to the long-time span of patients’ inclusion, surgical techniques were improved in the late stages, which may have an impact on data analysis.In conclusion, our study indicated that PD and PR were significantly effective in relieving the incidence and intensity of AKP and improving patient satisfaction in TKA at 3 months after TKA. Additionally, PD is more effective on alleviating AKP than PR.The authors would like to thank all the members of department of orthopedics, Cangzhou Hospital of Integrated TCM-WM for their great help and support.Xiaohui Ji designed the study and drafted the initial manuscript; Xiaodan Huang and Yingying Zhang coordinated and supervised data collection. Ming Zhao and Yaming Liu collected and analyzed data. Yanxin Cheng reviewed and revised the manuscript.Conceptualization: Xiaohui Ji.Data curation: Xiaohui Ji, Yingying Zhang, Yaming Liu.Formal analysis: Xiaodan Huang, Yingying Zhang, Yaming Liu.Funding acquisition: Yanxin Cheng.Investigation: Xiaodan Huang, Yanxin Cheng.Methodology: Yanxin Cheng.Resources: Ming Zhao.Software: Ming Zhao.Supervision: Ming Zhao.


Our understanding of the environmental and genetic factors contributing to the wide spectrum of neuropsychiatric disorders has significantly increased in recent years. Impairment of neuronal network activity during early development has been suggested as a contributor to the emergence of neuropsychiatric pathologies later in life. Still, the neurobiological substrates underlying these disorders remain yet to be fully understood and the lack of biomarkers for early diagnosis has impeded research into curative treatment options. Here, we briefly review current knowledge on potential biomarkers for emerging neuropsychiatric disease. Moreover, we summarize recent findings on aberrant activity patterns in the context of psychiatric disease, with a particular focus on their potential as early biomarkers of neuropathologies, an essential step towards pre-symptomatic diagnosis and, thus, early intervention. Neurodevelopmental disorders (NDDs) are highly prevalent diseases that affect about 3% of the population worldwide. They include disorders such as schizophrenia (SCZ), some forms of epilepsy, autism spectrum disorder (ASD), and attention deficit-hyperactivity disorder (ADHD). NDDs are characterized by a wide range of symptoms, including impairments in cognition, language, emotional processing, and motor functions , “disorganized” , and “negative” , as well as by cognitive deficits  imbalance has been proposed as a potential biomarker. E/I balance is essential for maintaining physiological network activity and disruptions of the pathways underlying excitation and/or inhibition have been described for patients with SCZ or ASD  in children with emerging ASD has shown promising results for improving adaptive behaviors later in life (Tiura et al., In this context, the need for reliable biomarkers of early dysfunction is evident. The wide spectrum of dynamic features inherent to neuronal oscillations might constitute a powerful tool for identifying, describing, and potentially even rerouting disorder-specific deficits. Specifically for SCZ, previous hypotheses have focused on altered neuronal activity during the prodromal period or during the time of the first episode of psychosis as a potential time window for intervention (Millan et al., Additionally, identifying developmental phases of aberrant activity in NDDs is a prerequisite for the rescue of physiological trajectories during development. Recently, manipulation of activity in a specific subset of prefrontal pyramidal neurons in young mice was shown to alter developmental trajectories and to have long-term effects on brain function and cognitive processes (Bitzenhofer et al., In conclusion, monitoring early neuronal oscillations is highly instrumental for understanding physiological and pathophysiological development. Early aberrations of neuronal activity patterns could serve as biomarkers of NDDs and thereby open up new avenues for non-invasive, pre-symptomatic diagnosis of at-risk patients, as well as provide potential tools for the directed treatment of emerging neuropsychiatric disease.AG and IH-O drafted, wrote, and edited the manuscript. All authors contributed to the article and approved the submitted version.