Sepsis is a common, life-threatening syndrome of physiologic, pathologic, and biochemical abnormalities that are caused by infection and propagated by a dysregulated immune response. In 2017, the estimated annual incidence of sepsis around the world was 508 cases per 100,000 , however, reported incidence rates vary significantly by country. A scoping review will identify knowledge gaps by systematically investigating the incidence of sepsis.This scoping review will be guided by the updated JBI (formerly Joanna Briggs Institute) methodology. We will search the following electronic databases: MEDLINE, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews/Central Register of Controlled Trials. In addition, we will search websites of trial and study registries. We will review titles and abstracts of potentially eligible studies and then full-texts by two independent reviewers. We will include any study that is focused on the incidence of sepsis or septic shock in any population. Data will be abstracted independently using pre-piloted data extraction forms, and we will present results according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols Extension for Scoping Reviews.The results of this review will be used to create a publicly available indexed and searchable electronic registry of existing sepsis research relating to incidence in neonates, children, and adults. With input from stakeholders, we will identify the implications of study findings for policy, practice, and research. Ethics approval was not required given this study reports on existing literature.The online version contains supplementary material available at 10.1186/s13643-022-02002-6. By cataloging what is known about the epidemiology of sepsis, we will clarify gaps in our understanding of its incidence and distribution.By including patients of all ages, this review may uncover differences in the epidemiology of sepsis between neonatal, pediatric, and adult populations.By describing rates across the last three decades, we may better understand if evolving definitions of sepsis have influenced reported incidence rates.Through the inclusion of all languages, we may better delineate differences in the international reporting of incidence rates of sepsis.Though consensus-based definitions of sepsis have evolved over the past 30 years –3, the cThe World Health Organization (WHO) estimates that sepsis affects over 30 million people each year, and is responsible for over 6 million deaths worldwide, including one million newborns . For 201Vulnerable populations such as those who live in poverty, or who have less education, higher unemployment, visible minority status, or more functional limitations have higher mortality rates from sepsis . AlthougThe main objectives of this scoping review are (1) to describe the epidemiology of sepsis , (2) to report incidence rates over time, and (3) to identify existing knowledge gaps to inform and guide future research. This scoping review will catalog existing knowledge and identify gaps, and as such it will be a fundamental infrastructure in informing and guiding future research as well as policy work in sepsis.https://osf.io/) upon acceptance.This is a protocol for a scoping review aimed at understanding what is known about the epidemiology of sepsis. Methods for inclusion and analysis of articles will be performed according to the updated JBI (formerly Joanna Briggs Institute) guide to scoping review methodology . The maiIdentify the types of available evidence of the epidemiology of sepsis;Clarify key concepts/definitions in the literature;Examine how research is conducted in the field of sepsis epidemiology;Identify and analyze knowledge gaps as fundamental infrastructure to inform and guide future research, policy work, ultimately with the aim of facilitating future sepsis research; andInform the conduct of a systematic review examining the epidemiology of sepsis.The specific objectives of this scoping review are:We will include citations if: (1) the study design is a non-randomized controlled trial, cohort study, case–control study, or cross-sectional study; (2) the study includes a population or subgroup of patients with defined sepsis or septic shock ; and (3) the population being described the report on the population incidence of sepsis . A preliminary exploratory review of studies examining sepsis will help refine the scope of the present protocol. We will not apply any publication date or language restrictions. Because our primary objective is to understand how the development of sepsis may vary among age groups, country of residence, socio-economic status, etc., there will be no eligibility criteria restricting the scoping review to specific populations.In collaboration with an experienced health science librarian, we will search the following databases from inception: MEDLINE, EMBASE, CINAHL, and Cochrane Library . To ensuThe unpublished literature  will also be searched . SpecifiAfter removal of duplicates, titles and abstracts of all search results will be assessed for inclusion against eligibility criteria. Titles/abstracts will be identified as “include,” “exclude,” or “maybe.” We will screen in two stages: first titles and abstracts, then full texts, and screening at both stages will be completed independently and in duplicate by two reviewers from the screening team. Prior to the screening of titles and abstracts (level 1 screening), the citation screening form will be calibrated through pilot testing with a random sample of 50 citations from the literature search by two reviewers, independently. The reviewer team will then independently review titles and abstracts, meet to discuss discrepancies, and make modifications to the eligibility criteria and screening form, and true screening will commence when at least 75% agreement is reached . Full teDuring this stage, we will collect key information about the selected articles using a predefined Data Extraction Form. The extraction form was first pilot-tested using five studies by two independent reviewers; the extracted data will include the following fields Table . The resWe define knowledge user (KU) engagement as individuals who may be affected by the research findings. We have recruited scientists from the Canadian Sepsis Network, a network of Canadian researchers with areas of expertise that include basic science, health services research, and health policy and specifically, individuals with expertise in neonatology and pediatrics.Partners will be engaged in the scoping review process including the refinement of study inclusion criteria as well as interpretation of findings to inform dissemination activities. Activities will be sequential, and findings will inform the next steps.No patient was involved.Scoping reviews do not include quantitative synthesis of results, but rather characterize the existing literature and identify research gaps. A narrative report will be produced to summarize the extracted data around the following outcomes for each of the populations studied : region of study, data sets used, incidence, associated definitions used, and changes reported in incidence over time. These results will be described in relation to the research question and in the context of the overall study purpose. Descriptive frequencies of the aims/results of the findings will be reported, and visually mapped to display the possible concentrations of sepsis research exploring incidence among certain populations and geographical regions. Gap identification will detect areas, such as countries that lack data on the incidence of sepsis in specific populations , and if there is a paucity of data on significant sepsis-related conditions.Since the scoping review will synthesize information from available publications, it does not require ethical approval. The end-users identified, in addition to individual sepsis investigators, include the Canadian Sepsis Foundation, British Columbia Patient Safety and Quality Council, Canadian Critical Care Society, Canadian Critical Care Trials Group, Global Sepsis Alliance, Chief Medical Officers of Health in Canadian provinces, Canadian Association of Emergency Physicians, Canadian Critical Care Translational Biology Group and the Network of Canadian Researchers.https://www.sepsiscanada.ca/).Potential barriers to study uptake include (1) lack of awareness and (2) lack of time. To circumvent these barriers, an article reporting the results of the scoping review will be submitted for publication to a scientific peer-reviewed journal; the research team will conduct webinars reporting study findings, investigators will present results at national and international meetings, and lastly, an organized twitter campaign will further awareness of study results. In recognizing the barrier of a lack of time, a one-page summary tailored to different audiences will be crafted and made available. We will organize collated information into a publicly available indexed and searchable electronic registry of existing sepsis research. This registry will be publicly available through the Sepsis Research Network’s website (Additional file 1: Appendix 1. Search strings for Medline and EMBASE.


Today, humanity is facing serious problems due to the environmental pollution. Several tons of plastic or industrial wastes are dumped randomly in nature, polluting waters and soils, thus creating many health problems for people and all living things. To keep the Earth clean, we need to adopt eco-friendly strategies sustaining human and environmental health. Green nanotechnology—the science of the future—can help to prevent future environmental problems and improve the general quality of life and human well-being. In addition, bioinspiration and biomimetics became new trends in green nanotechnology for the “green” development of multifunctional materials with potential applications in the biomedical field and in environmental protection ,2,3.in vitro and in vivo tests to determine their effectiveness as antimicrobial agents against pathogenic bacteria, fungi and viruses, or as antioxidant and anti-cancer agents.It is known that, since ancient times, most sources of natural substances with healing effects are of plant origin. Plants contain a wide range of substances, which have been used for millennia in traditional medicine ,5. ReseaThis special issue “Novel Green Nanotechnologies Applied in Environmental Protection and Health” aimed to highlight many aspects related to “green” approaches to design innovative materials/systems, and eco-friendly strategies for applications in Environmental Protection and Health. Interesting topics are proposed. By using natural resources and recycling food and vegetal wastes, and also the bioinspiration and biomimetics for development of novel materials, the environment pollution can be avoided, thus preventing severe problems affecting human health.This Special Issue kindly invites authors to contribute with original research articles and review papers describing novel green nanotechnologies applied to design eco-friendly materials, by exploiting natural resources and recycling food and vegetal wastes, and converting them into valuable materials with applications in various fields.Eco-nano technologies and advanced materials;Environmental and biomedical applications of “green” nanomaterials;Eco-friendly strategies for development of (bio)composite/(bio)polymeric materials;Biomedical applications of nanoparticles/materials;Nanoparticles for drug delivery systems;Biological activity of nanoparticles;“Green” materials and technologies for electronics;Bioinspiration and biomimetics for development of novel materials;Bioplastics;Eco-friendly packaging materials;Biopesticides;Photocatalysis;Wastewater treatment;Eco-Friendly Corrosion Inhibitors.Potential topics include, but are not limited to the following:


Phase 2 comprised two online surveys to (1) reduce the list to 37 research priorities which achieved consensus (>75% 2-point agreement) and had high mean importance ratings (n = 116 participants) and (2) determine the most important priorities, barriers, and enablers (n = 90 participants). The top ten ranked research priorities for the overall sample and sub-groups  were identified. Priorities focused on: tumour biology, pre-clinical research, clinical and translational research, and supportive care. Variations were seen between sub-groups. The top ten barriers to conducting brain tumour research related to funding and resources, accessibility and awareness of research, collaboration, and process. The top ten research enablers were funding and resources, collaboration, and workforce. The broad list of research priorities identified by this Delphi study, together with how consumers, health professionals, and researchers prioritised items differently, and provides an evidence-based research agenda for brain tumour research that is needed across a wide range of areas.The aim of this project was to determine research priorities, barriers, and enablers for adult primary brain tumour research in Australia and New Zealand. Consumers, health professionals, and researchers were invited to participate in a two-phase modified Delphi study. Phase 1 comprised an initial online survey ( The term adult primary brain tumours includes both malignant and benign tumours. The Australian Institute of Health and Welfare estimated that 1879 new cases of adult brain tumours would be diagnosed and 1518 people would die from brain cancer in Australia in 2020 . AlthougAlthough brain tumours are classified as rare cancers, there are currently a limited number of research grant opportunities available in neuro-oncology through the Brain Cancer Mission and Australian Medical Research Future Funding and other funding opportunities. Nevertheless, funding and resources for brain tumour research remain limited compared to that available for other tumour types ,8. Theren = 18 health professional participants and 2 consumers) to determine research priorities for adult gliomas in Australia in 2010  = 10.115, p = 0.006). There was a significant effect of group on age overall (H [p = 0.006); consumers were significantly older (Median = 55.0 years) compared with health professionals  and researchers . No other pairwise comparisons were significant. Cross tabulations of role by location and country were not significantly different.There was a significantly greater proportion of female consumers (75%) than female health professionals . Cross tabulations of role by location and country were not significantly different. There was a significant effect of group/role on age overall (H [p = 0.019); consumers were significantly older (Median = 54.5 years) compared with researchers . No other pairwise comparisons were significant.Of 116 eligible participants, 100 began the Step 2 survey and 90  provided responses (response rate = 78%) that were used for the analysis . All health professionals in this step were clinicians  actively involved in clinical trials. See p = 0.577).After Step 1, 23 items were removed because they met the criteria for deletion (<75% agreement and mean <3.0).p = 1.000), barriers (p = 0.628) or enablers selected (p = 0.059), or priorities ranked (p = 1.000) (Max. possible = 10); or priorities (p = 0.294) or enablers (p = 0.538) opted for COGNO (Max. possible = 5). More consumers selected ‘unable to comment’ for the question about selected research priorities for COGNO .There were no significant differences between groups in the total number of options selected for each of the following questions: priorities , barriers  or enablers , or ranking priorities ; or enablers  for COGNO. Gender or role were not significant predictors for missing opting priorities for COGNO . However, a significantly greater proportion of regional/rural (29%) or remote (50%) participants missed opting for priorities for COGNO compared with participants located in a major city .A sensitivity analysis was performed on the type of participants who missed questions. Gender, location, or role were not significant predictors for missing the questions for selecting priorities  or enablers , or opting priorities  or enablers  for COGNO. Participants who missed ranking priorities were significantly older (Median = 62.5) compared with participants who answered (Median = 51.0) .Age did not significantly predict missing the questions for selecting priorities , availability, accessibility and awareness (n = 2), collaboration (n = 2), and process (n = 1). The top five barriers for the overall group were: lack of research funding; limited research resources; lack of access to international trials; failure to fully integrate lab research with clinical trials; and limited research opportunities for rare tumours with a low caseload in Australia and New Zealand.Lack of research funding was the most frequently selected barrier within each sub-group and for the overall group. Four of the consumer groups’ and three of the researcher groups’ equal top five barriers were in the funding and resources category. The workforce-related barriers of lack of time and job insecurity were within the top five barriers for the health professional and researcher groups respectively.n = 5), collaboration (n = 3), and workforce (n = 2). The first four enablers for the overall group, and the health professional and consumer sub-groups, were in the funding and resources category. The equal top five research enablers for the overall group were specific brain cancer research funding ; dedicated brain tumour clinics and centres of excellence; government funding; national brain tumour biobank and clinical registry funding; protected research time for clinicians and academics; and centralised mechanisms for research and clinical trials .The two enablers (1) specific funding allocated to brain cancer research, in recognition of the additional challenges to conducting research in a rare (but high impact) disease, and (2) dedicated brain tumour clinics and centres of excellence were in the top five selected enablers within each sub-group and for the overall group.This Delphi study determined the current top research priorities for adult brain tumours in Australia and Zealand. The overall top five ranked research priorities in the current study were: conducting clinical trials that include relevant patient-reported outcomes; understanding the tumour microenvironment with the aim of reducing immunosuppression and facilitating immunotherapy; exploring the effectiveness of precision medicine/personalised treatment based on genomic profiling; conducting pre-clinical research to identify actionable drivers (and new molecular targets) for brain tumour therapy, and investigating advanced neuro-oncology imaging for diagnosis and treatment response monitoring.A strength of this study is that we have included opinions from many participants, including a large cohort of health consumers. For a niche area, such as rare primary brain tumours, we had strong representation across all major clinical disciplines, researchers, and consumers. There was a variation between consumers, health professionals, and researchers’ rankings of priorities, including two priorities in the top 10 that were significantly different, which became most apparent in priorities ranked 11th to 37th by the overall group. The following priorities were in the top 10 for all three groups: understanding the tumour microenvironment with the aim of reducing immunosuppression, and facilitating immunotherapy, exploring the effectiveness of precision medicine/personalised treatment based on genomic profiling, and investigating reasons for treatment resistance.Conducting clinical trials that include relevant patient-reported outcomes  was ranked highest overall, ranked second by consumers, and first by researchers. Interestingly, this was not identified in the top 10 priorities by health professionals (ranked 16th). All health professionals who participated in this final step of the study were clinicians actively involved in clinical trials. Health professionals may have put this item as a lower priority because they focus on treatment outcomes in their day-to-day practice and the underlying evidence-based generated from research which has outcomes using non-patient reported data such as survival, toxicities, and recurrence. There has been a recent drive to include patient-reported outcomes in clinical trial grant applications, and also in clinical practice as a measure of health-care quality ; COGNO hImmunotherapy is a current medical research priority in many solid cancers with two topics in the top 10 priorities focusing on this. The last decade has seen exponential growth in immunotherapy treatments and research which likely explains the emergence of this topic in this Delphi study. Brown et al.  recentlyA top priority identified in the current study was to explore the effectiveness of precision medicine/personalised treatment based on genomic profiling. This builds on the previous priority identified in 2010 as determining the molecular and pharmacogenetic determinants of treatment response to enable the development of tailored treatment regimens that offer improved quality of life and survival . A recenThe research priority of conducting pre-clinical research to identify actionable drivers (and new molecular targets) for brain tumour therapy builds on the previous Delphi study in 2010  which reAnalogous to the findings from the 2010 Delphi study , which hIn 2010, the highest-ranked research priority was the formation of a national glioma collaborative network  . The curHealth professionals ranked priorities in the areas of clinical and translational research studies significantly higher compared with other groups, including phase 0 studies and using liquid biopsies for diagnosis and monitoring. From the consumer perspective, there is not yet widespread awareness of these clinical trial and translational research topics as they are not mainstream and would not routinely be discussed with their oncologists. Recently, Sanai  providedResearchers ranked developing psychosocial interventions for unmet needs and evaluation of optimal models of care coordination in their top 5 priorities and significantly higher than either health professionals or consumers (note that 47% of researchers produced psycho-oncology research). Both these priorities build on the 2010 Delphi study  which hiConsumers ranked the following research priorities significantly higher than health professionals and/or researchers: understanding the causes of adult brain tumour development and conducting drug repurposing studies in adult brain tumours. When diagnosed with a brain tumour or when caring for someone with a brain tumour, patients and carers may be trying to process and construct meaning around the cause of their diagnosis to help them cope and adjust to their recent diagnosis . AdditioOther top 10 research priorities identified in the current study that were not included in the 2010 study include investigating reasons for treatment resistance and developing pre-clinical models and strategies to enhance blood-brain barrier penetration for novel drugs. Several studies have collected or are collecting molecular information to enable further understanding of gliomas and treatments ,36. The Additionally, this study identified the common barriers and enablers for adult brain tumour research. Five of the top ten research barriers and enablers are related to the funding and resources category, highlighting that this is an important area of need for brain tumour research. Funding and resources-related barriers included that trial site funding was tied to pharmaceutical studies’ income or there was a lack of or limited research funding, research resources, infrastructure (funding early career and student researchers), and a comprehensive database of all brain tumours. These findings build on a previous survey conducted with Australian medical students which identified that barriers to incorporating research into their medical careers included low funding, job insecurity, and low salaries . EnablerThe key findings of this Delphi study will be integral to informing the strategic plan for COGNO’s research priority focus areas over the coming 5–10 years. The research priorities highlight the areas of opportunities for potential breakthrough developments for primary brain tumours, which should aim to ultimately improve the patient and carer experience, and include novel targeted and immune therapeutics; advanced imaging and liquid biopsy technologies, improved understanding of pharmacokinetics/pharmacodynamics, tumour microenvironment and resistance mechanisms, and successful translation of research findings into national practice. Leveraging a strategic plan, there is potential for researchers to make meaningful contributions to the international research effort in these domains. Before proceeding, it will be important for COGNO to establish the research currently underway, both in Australia and internationally, which has synergy with these domains, to determine and focus on areas where Australia and/or New Zealand will have a competitive advantage, and to establish pragmatic approaches to attenuate the effect of research barriers. It is acknowledged that the differences in consumers, health professionals and researchers’ rankings of priorities need to be considered in creating and communicating a plan that ensures the efficient use of scarce resources. Arguably, the feasibility and tractability of the research priority should also be considered. Some of the priorities, such as benchmarking and quality measures, are service developments which could be best supported through public funding. The study findings also provide evidence with which to advocate to the various funding bodies in Australia and New Zealand and organisations working in the brain tumour space.This study was limited to Australian and New Zealand participants. The response rate in this study, when it was possible to calculate, was comparable to rates reported in another Australian Delphi study involving a similar participant group . HoweverThis study provides a summary of research priorities for adult brain tumours from the perspectives of consumers, health professionals, and researchers. The overall top five ranked research priorities focused on conducting clinical trials that include relevant patient reported outcomes, understanding the tumour microenvironment to facilitate immunotherapy, exploring the effectiveness of precision medicine/personalised treatment based on genomic profiling, conducting pre-clinical research to identify actionable drivers for brain tumour therapy, and investigating advanced neuro-oncology imaging for diagnosis and treatment response monitoring. The broad list of research priorities identified by this Delphi study, together with how consumers, health professionals, and researchers prioritised items differently, demonstrates that the brain tumour research portfolio is broad and research is needed in a wide range of areas. Funding and resources were highlighted as an important area of need with many research barriers and enablers in these categories. Designing research projects which seek to incorporate and address these priorities will lead to improved outcomes for patients diagnosed with adult brain tumours. We have also identified barriers and enablers to conducting research which will assist future planning in this area.Findings from a part of this study were presented at the 14th COGNO Annual Scientific Meeting (2022) as an oral presentation.


Posttraumatic stress disorder (PTSD) is a debilitating disorder requiring timely diagnosis and treatment, with special attention needed for Black populations in the U.S. Yet, stakeholders often fail to recognize Black communities' heterogeneous ethnic composition, thus not allowing diverse sociocultural realities to inform PTSD interventions. This study aims to characterize sex and ethnic differences in lifetime trauma exposure, lifetime PTSD diagnosis and symptoms, and help-seeking among the African Americans and Black Caribbeans in the U.S.n = 3,570) and Black Caribbean  adults. 44.5% of respondents were men and 55.5% were women. Logistic regression was utilized to investigate the impact of traumatic events on PTSD.This study relied on data from the National Survey of American Life 2001–2003 (NSAL) to investigate the lifetime exposure to traumatic events and prevalence of a clinical PTSD diagnosis based on the DSM-IV among African American (Several ethnic and sex differences in exposure to potentially traumatic events were identified. African American respondents were more likely to experience spousal abuse and toxin exposure than their Black Caribbean counterparts. Black Caribbeans reported higher lifetime exposure to muggings, natural disasters, harsh parental discipline, being a civilian living in terror and/or being a refugee than African American respondents. Specific to sex, Black men reported more events of combat, a peacekeeper/relief worker, being mugged, toxin exposure, seeing atrocities, and/or injuring someone. Black women were more likely to have been rape/sexual assault and/or intimate partner violence victims. The assaultive violence trauma type was most predictive of lifetime PTSD diagnosis among Black Americans. African American women were more likely to report PTSD symptoms than men, with almost no significant differences in Black Caribbean men and women. Approximately half of Black Americans sought help for their worst traumatic event, commonly engaging family/friends, psychiatrists, and mental health professionals. Further, there were almost no ethnic and sex differences related to professional and non-professional help sought.Future PTSD-related research should aim to characterize the heterogenous experiences of potentially traumatic events within different Black communities. Clinicians working with Black clients should strive to understand the limitations within their tools/interventions in meeting the needs of diverse groups. When exposed to an event, either directly or indirectly, that causes stress, fear or hopelessness, it is a natural human response to experience a range of negative physical and psychological effects. However, for 6.8% of Americans, these negative effects lead to lasting impacts on one's quality of life and a subsequent diagnosis of posttraumatic stress disorder . Known In consideration of PTSD and ethnoracial identity, a review by Asnaani and Hall-Clark  notes liAs past studies have shown, Black people in the United States have the highest lifetime prevalence of PTSD –31. HoweA failure to understand and recognize ethnoracial heterogeneity can prove a harmful oversight in ensuring underserved groups have access to the culturally relevant interventions they need to safely and efficaciously treat their PTSD. To this point, some ground has been made: experts acknowledge that the vast amount of research and research-informed outputs generated to date were created with/for majority White populations . Many arSimilarly, the experiences of men and women in terms of potential traumatic event-type exposure, PTSD development, and resultant treatment outcomes can be very different between the sexes. Absent consideration of ethnicity, a landmark meta-analysis by Tolin and Foa considering sex-specific risk to traumatic events and PTSD, found men were more likely than women to report having experienced a potentially traumatic life-event . NeverthNational Survey of American Life (NSAL) 2001–2003, regarding men and women of African (“African Americans”) and Caribbean decent (“Black Caribbeans”). While almost 20 years old, NSAL remains the most comprehensive and detailed study of Black American mental health ever completed and one of the only that allows for such ethnic subgroup analysis. Once presented, the article will situate these findings within the broader body of research and present actionable recommendations for researchers and clinicians looking to better serve these diverse communities.For said reasons, this study aims to consolidate and supplement the existing literature on sex and ethnoracial differences within Black Americans related to traumatic event exposure over the lifespan, as well as the lifetime diagnosis of PTSD, its symptomatology, and related help-seeking behaviors. To do so, the article will first present related findings from the Collaborative Psychiatric Epidemiology Surveys (CPES). The primary objective of the CPES initiative was to collect data regarding the prevalence of mental disorders, impairments associated with these disorders, and their treatment patterns from representative samples of Americans. Diagnostic interviews were undertaken between February 2001 and March 2003 by trained interviewers from the participants' local communities, with race/ethnic matching employed to optimize the interview experience. Moreover, NSAL focuses on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) disorders, psychological distress, and service use among African American and Black Caribbean adults. At the time of its collection, the NSAL was considered the “most comprehensive and detailed study of mental health of Americans of African descent ever completed” and this remains true today . In a 2Black Caribbeans reported greater traumatic exposure to natural disasters. Geographically, the Caribbean islands are at greater risk of hurricanes, floods, landslides, droughts, etc. . In addiCorporal punishment is a term used to characterize physically or psychologically violent disciplinary acts exhibited by an authority figure, with the intention of modifying a child's undesirable behavior . BreslaIn consideration of Black Americans, there is some comparative research on trauma event types and lifetime PTSD diagnosis risk. One study by McLaughlin and colleagues found that while Black Americans did have higher odds of lifetime PTSD than other ethnoracial groups, this difference was not significant when adjusting for trauma event type . Yet anoThis study found African American women were significantly more likely than their male counterparts to suffer from PTSD symptoms. Valentine and colleagues  worked tAbsent ethnicity, there is some research considering broader sex differences in PTSD symptomatology. Generally, Guina and team found that among those with experiences of trauma, women present with more severe symptoms . HoweverOther studies looking more granularly at sex differences in specific trauma types have maintained that sex differences exist. For instance, a study considering active-duty military personnel found women reported greater distress than their male counterparts on most PTSD symptoms (except hypervigilance) after traumatic combat-related events . AnotherIn consideration of why these sex differences in PTSD symptomatology exist, Olff and team suggest several hypotheses , includiThis study found near half of Black Americans sought professional assistance for their worst traumatic event. For the many that did not, most believed the problem would resolve on its own, preferred to solve the problem by themselves, or doubted treatment could help. In a recent systematic review by Smith and team , researcAlthough Smith's review did not focus exclusively on findings related to Black communities, similar reasons have been given by African Americans for failing to obtain treatment for other conditions . Furtheclinicians should (1) understand that many of the evidence-based tools/interventions used to assess/treat PTSD have not been informed by/validated for use in diverse groups. If they have, it is likely not to the level of granularity so as to meet the unique needs of diverse subpopulations and/or sexes . (2) Clinicians should also be sure to sensitively assess client risk to trauma types most likely to be experienced based on their sex and ethnic identity. (3) When available, clinicians should employ ethnicity/culture or sex-specific interventions for treatment of PTSD. Moreover, when welcomed by the client, clinicians should consider the involvement of other supportive professionals  and non-professionals  in the therapeutic process. (4) Clinicians should recognize when accessing external resources may be more appropriate or fill a need for the client that the clinician cannot . In doing so, the clinician should familiarize themselves with local cultural and sex appropriate support services/resources available for some of the most frequently reported trauma event types. For example, culturally safe battered women shelters, Black online support groups for those who have lost a loved one, etc. Finally, (5) clinicians should proactively assess for and address any barriers or reasons for ambivalence within clients in engaging mental health supports .In light of the above findings, when treating patients of colour suffering from PTSD, Researchers also have an important role to play in ensuring Black communities receive the quality care they deserve. To do this, the authors recommend (1) future work be undertaken to better characterize the heterogenous experiences of traumatic events and PTSD within different Black communities, including people with roots to the Caribbean, Africa, South America, and Central America. Moreover, (2) additional work should be undertaken to capture sex and gender differences more wholly within people of colour suffering from PTSD (LGBTQ+ members included). For both (1) and (2) this consists of prevalence rates, traumatic event type exposure differences, symptom severity, intervention outcomes, help-seeking behaviours, and treatment barriers. (3) When communicating sample characteristics and study outcomes within trauma research but also more broadly, researchers should also consider “diversity within diversity” and report ethnic and sex subgroup findings. Lastly, (4) there is a need for updated statistics on the Black American experience through the administration of an updated NSAL-like national survey , due partly to fears and suspicions concerning questions about possible immigration status [, with supplemental support from the Office of Behavioral and Social Science Research at the National Institutes of Health (NIH) and the University of Michigan. The preparation of this article was supported by a grant from the National Institute on Aging to RTJ (P30 AG015281). This research was undertaken, in part, thanks to funding from the Canada Research Chairs Program, Canadian Institutes of Health Research (CIHR) grant number 950-232127 (MTW). Also, Canada Graduate Scholarships-Doctoral (CGS-D) Program, Social Sciences and Humanities Research Council (SSHRC) Grant Number 767-2021-2327 (SGR).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.


Reformulating packaged foods has the potential to improve the nutrient density of the global diet. The present perspective illustrates The Kraft Heinz Company’s approach to product (re)formulation to develop healthier product lines that are lower in saturated fats, total sugars, and sodium, and contain health promoting components. Here we present the rationale for The Kraft Heinz Company’s global nutrition targets used for the global innovation and renovation of foods and beverages. The global nutrition targets use a category specific approach to set maximum levels for the main nutrients of public health concern: saturated fat, total sugars and sodium, taking into account product characteristics  as well as regulatory, technological, sensory and safety constraints. Benchmarking examples illustrate how the nutrition targets are positioned within the United States, France, and Australia. These global nutrition targets serve as part of The Kraft Heinz Company’s environmental, social and governance nutrition commitments and demonstrates how the food industry is improving the nutritional value of packaged foods and beverages both now and into the future. NutrienLocal and regional regulatory bodies, including Public Health England , the FooFood and beverage manufacturers are using a variety of quantitative tools to develop reformulation targets and to benchmark their progress toward healthier product lines , 13. AmoToday NP methods have been further developed by the food industry to provide both direction and benchmarking for product innovation and (re)formulation. Among industry-driven NP models are those developed by Unilever (now Choices) , Nestlé Ongoing self-review of nutrient density of the global food supply has been spurred by the Access to Nutrition Initiative (ATNI) . ATNI haThe present perspective addresses The Kraft Heinz Company’s (KHC) global product portfolio which is composed of 51 separate product categories that align with over 200 brands that are sold in nearly 200 countries. KHC has developed global nutrition targets for each product category, focusing on upper limits for energy, sodium, total sugar, and saturated fat. These standards have been used to screen existing Kraft Heinz products for nutritional value and to set achievable and impactful targets for product reformulation that are category specific. Assuring transparency and disseminating the current and proposed nutrient standards is the purpose of the present report.1.1.The development of nutrition targets for innovation and renovation at KHC included setting target levels for the main nutrients of public health concern: saturated fat, total sugars, and sodium. Several key factors were considered, including the breadth of existing KHC products, their role in the diet, food ingredients, regulatory standards, technical considerations, taste, performance, and results from the benchmarking of foods.Consideration was given to nutrient guidelines recommended by the WHO , Pan AmeFirst, a category-specific approach was used based on the global KHC portfolio due to the wide variety of foods and beverages sold. Targets for nutrients of public health concern were developed for each product category. These included guidelines for optimal calories per 100 g (100 mL for beverages) and maximum amounts of sodium, total sugar, and saturated fat across all product lines, as described in Second, KHC nutrition targets had to be relevant to the dietary role of KHC products and to the eating occasion. The global nutrition targets reflect the dietary role of the product as outlined in national dietary guidelines , 24, 25.Third, nutrient standards for a given product category are governed by the nutrient content within the category. The KHC global nutrition targets recognize that some ingredients can contribute vitamins and minerals along with nutrients of concern. For example, milk found in cheese and dairy products can be a source of both saturated fat and calcium. The sugar in 100% juice is considered naturally occurring in the fruit, while juice drinks may contain added sugars.Fourth, some products are subject to regulatory standards, such as standards of identity adopted under Codex  and enfoFifth there are technical challenges. For example, sodium has multiple functions in food, such as extending shelf life, stabilizing microbiological activity, enhancing flavor and palatability, and improving food structure and texture , 30. TheThe KHC regional nutrition guidelines for leading markets, such as the United States, Europe, Australia, and New Zealand were used as a starting point to set the global nutrition targets. The KHC global nutrition targets  are bein1.2.Ketchup, mayonnaise and French fries/fried potatoes are popular foods worldwide and contribute markedly to KHC sales volume. These products were selected to illustrate how KHC global nutrition targets compare to the current market options available in the United States, France, and Australia.th percentile cut-points of the distribution for currently available products. For a normal distribution, the 85th percentile is one standard deviation above the mean.Nutrient composition data for the United States market came from the U.S. Department of Agriculture (USDA) Branded Food Products Database . Items wth percentile cut-point in both United States and French databases. For mayonnaise, KHC sodium target was below the cut-point in the United States but above the cut-point in French data. For French fries, the KHC sodium target was above the cut-points both in the United States and in French databases. KHC target for added sugar in ketchup was at ~85th percentile cut-point for both data sets; by contrast KHC targets for added sugar in mayonnaise and French fries were substantially higher. The KHC target for saturated fat in mayonnaise was below the United States but above the French cut-point.KHC target for sodium in ketchup was well below the 85These data illustrate the difficulty of reformulating products across different markets and product lines. First, based on our analyses of nutrient composition databases, these products in France contained lower amounts of saturated fats, sodium, and total sugars. Whether this was related to diet quality is not clear, since dietary intake data was not available. Second, product categories are not always totally comparable across different markets. For example, KHC nutrition targets are lower than observed values in 15% of products for sodium in ketchup and, in the United States only, for sodium and saturated fats in mayonnaise and sugar in ketchup. The KHC sugar target for mayonnaise is above the market reality, as the KHC subcategory for spoonable dressings and mayonnaise includes sauces other than mayonnaise  that may contain sugar. Reassessing the targets for spoonable dressings and mayonnaise could be considered for the future.via the Foodswitch app, it was observed that 20% of ketchups  had greater than or equal to 3.5 health stars and therefore classified by ATNI as a “healthy” product (n = 21) had <700 mg sodium and <24 g sugars per 100 g.Currently there is no publicly available Australian branded food database for use by consumers, researchers, or businesses. As such, the George Institute for Global Health in Australia FoodSwitch smartphone app  was used product . On asse2.Product reformulation and innovation provides an opportunity for the food industry to improve the nutritional value of packaged foods. Research suggests that dietary behavior change observed in some consumers following product reformulation does not offset the overall benefits of product reformulation on dietary intakes at the population level . Indeed,The WHO’s recommendation is to achieve a 30% relative reduction in mean population intake of sodium by 2025 . The WHOSensory and consumer research are essential in product innovation. This is to ensure that reformulated foods will meet consumers’ expectations and be consumed, and therefore have a dietary impact and public health benefit. Sensory evaluation is a science that measures the reactions to products as perceived by sight, smell, taste, touch and hearing . DiffereAnother aspect of product (re)formulation is an increase in positive nutrients and/or food components  to improve overall nutrient density.Product formulation can be an efficient means of optimizing both nutrient content and nutrient bioavailability within a food. For instance, adding oil to tomatoes favors the absorption of lycopene, a potent antioxidant carotenoid present in high amounts in tomatoes . AdditioKHC’s 2025 ESG nutrition commitments include: achieve 85% compliance with KHC’s global nutrition targets, reduce total sugar in products by more than 60 million pounds across the global portfolio and reduce sodium by 5% in Kraft BBQ sauce and salad dressings, in North America .As one example of sugar reduction, in August 2022, KHC’s CapriSun in the United States and Canada, launched reformulated juice drink pouches with an average of 40% less sugar than the original product. Each 6 fl. oz. serving (177 mL) now has an average of 8 g of total sugars and 5 g of added sugars. The sugar reduction in CapriSun accounts for more than half of the proposed sugar commitment.Key nutrition priorities for KHC over the coming years are to continue to gradually reduce nutrients of public health concern  and increase positive nutrients and food groups, while considering consumer demand related to taste and texture. Furthermore, the benchmarking of products additional to those already presented, that make up the major volume of sales of KHC could suggest improvements of global nutrition targets. For maximum public health benefit, the planned gradual improvements in nutrient density need to occur without provoking major changes in consumer food choice and purchasing behavior.Mac and Cheese), vegetable and legume based soups with 15 g of plant protein per serve (Heinz Plant Proteinz), Classico tomato sauces with ½ cup of vegetables per serving from tomatoes, meal-type products (SmartOnes entrees), containing ½ cup vegetables per serving, and whole-grain offerings from Lunchables products in the form of crackers.Where feasible, KHC can also explore including nutrients  and food groups to encourage in the global nutrition targets. Current examples of products with food groups to encourage include 100% whole wheat macaroni formulation will have a global reach since these nutrition targets are being applied to the KHC’s global food and beverage portfolio. The present examples from branded food composition datasets from the United States and France show that the targets are being met by products among the major volume of sales of KHC; ketchup, mayonnaise and French fried potatoes. Improving nutrient composition of frequently eaten foods has the potential to improve overall dietary intake. Further enhancements of the KHC product portfolio will involve the continued reduction in sodium and sugar content and the addition of wholesome food components to packaged foods. There is also potential to transform the existing global nutrition targets into a KHC nutrient density score.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.All authors contributed to the manuscript design, analysis of data, writing and approval of the final manuscript.This study was fully funded by The Kraft Heinz Company.LY, BE, and AB were full time employees of The Kraft Heinz Company during the manuscript preparation and submission. VB is a member of The Kraft Heinz Global Nutrition Advisory Group and the owner of VAB-nutrition, a consultancy company providing nutrition-related scientific support to food industries. SC is a member of The Kraft Heinz Global Nutrition Advisory Group and provides consulting services to industry with interests in food labeling and sustainable diets. AD is the original developer of the Nutrient Rich Food (NRF) index, a nutrient profiling model. That work was supported at the time by the Nutrient Rich Coalition whose members were The Beef Checkoff Program through the National Cattlemen’s Beef Association, California Avocado Commission, California Kiwifruit, California Strawberry Commission, Egg Nutrition Center, Florida Department of Citrus, Grain Foods Foundation, National Dairy Council, National Pork Board, United States Potato Board, Wheat Foods Council, and Wild Blueberry Association of North America. AD is a member of Nestlé Scientific Advisory Board and invited member of the Quality Carbohydrate Coalition supported by APRE and Potatoes USA. AD is a member of The Kraft Heinz Global External Nutrition Advisory Group. AD has received grants, contracts, and honoraria from entities both public and private with an interest in nutrient density metrics and nutrient profiling of foods.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.


Allostatic load refers to cumulative neuroendocrine burden and has been postulated to mediate and moderate physiological and psychological stress-related responses. This may have important implications for the risk of preterm birth. This systematic review examines the evidence on the association between prenatal allostatic load and preterm birth.A comprehensive search of seven electronic databases was conducted from inception to August 23, 2022 to identify all English-language observational and mixed methods studies examining allostatic load and preterm birth with no year or geographic restrictions.Studies were included if they measured allostatic load, evaluated as the cumulative effect of any combination of more than one allostatic load biomarker, during pregnancy. Studies must have observed preterm birth, defined as < 37 weeks' gestational age, as a primary or secondary outcome of interest.The Quality In Prognosis Studies tool was used to evaluate risk of bias within included studies. A narrative synthesis was conducted to explore potential associations between allostatic load and preterm birth, and sources of heterogeneity.Three prospective cohort studies were identified and revealed mixed evidence for an association between allostatic load and preterm birth. One study reported a statistically significant association while the other two studies reported little to no evidence for an association. Heterogeneity in when and how allostatic load was measured, limitations in study design and cohort socio-demographics may have contributed to the mixed evidence.This review provides insight into key individual-, community-, and study-level characteristics that may influence the association between allostatic load and preterm birth. Knowledge gaps are identified as foci for future research, including heterogeneity in allostatic load biomarkers and allostatic load index algorithms as well as pregnancy-specific considerations for allostatic load measurement. Further investigation of the allostatic load framework in the context of perinatal mental health is needed to advance understandings of maternal, infant, and child health.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020208990, PROSPERO, identifier: CRD42020208990. Preterm infants (babies born prior to 37 weeks' gestation), often encounter complications of prematurity  that are associated with higher preterm-related morbidity and mortality rates when compared to infants born at term  with experience in conducting systematic reviews with input from a clinical expert (SSP), and integrated feedback from experts in the field. ® and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials (OVID), APA PsycINFO (OVID), CINAHL Plus with Full Text (Ebsco), Scopus (Elsevier), and Web of Science Core Collection. Databases were searched from inception to August 23, 2022 with no restrictions by year or geographic location. Additional papers were identified through backward searches (reference list of included studies) and forward searches  of studies cited in the included papers.Databases that were searched included MEDLINE®, a web-based software for systematic reviews. Inclusion criteria for title and abstract screening were studies that focused on AL evaluated as the cumulative effects of any combination of AL biomarkers . AL was characterized as measuring physiological dysregulation across multiple systems   resulted in eight reviewers  involved at different points in the review process. Prior to screening within Covidence, the inclusion and exclusion criteria were evaluated by screening groups of 50 randomly selected title and abstracts on Microsoft ExcelThe main exposure variable was prenatal AL. We extracted all AL biomarkers and algorithms reported in included studies. The primary outcome of interest was preterm birth, defined as birth < 37 weeks' gestation with gestational age determined using ultrasound measurement. We extracted both categorical and continuous outcome data.®  independently reviewed all included studies and extracted data into a standardized Microsoft ExcelWe used the Quality In Prognosis Studies (QUIPS) tool , and other measures of association  were extracted from included studies and are contextualized in the tables and narrative synthesis. For studies that used multiple linear regression models, only data from final models are presented.n = 246), inappropriate study population (n = 22), and inappropriate study design (n = 55). Several studies . In Sayre's , although first, second-, and third-trimester AL indexes were not statistically significant predictors of preterm birth  in logistic regression models. In the Wallace and Harville  Canadian Institutes of Health Research (CIHR) project grant : SSP is the nominated principal investigator, KS and ISY are principal applicants, and AD, SL, and JWM are co-applicants; and (2) Startup Grant, Faculty of Health, York University. These funding sources supported the Research Assistants who worked with the team on this systematic review. These funding sources were not involved in the study design, data collection and analysis, writing of the report, or decisions to submit the article.Authors GSP and AC were Research Assistants who were paid through the CIHR Project Grant and Startup Grant, Faculty of Health, York University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


As social networks shrink with age, older adults value the importance of interpersonal relationships with close others, such as partners, family and friends. Previous studies focused on perpetrators' and victims' characteristics; however, few studies examined the relationships with close others and the incidence of elder mistreatment. This study used the National Social Life, Health, and Aging Project Wave 1 data (2005-06) to examine the correlations between relationship quality with close others and the occurrence of mistreatment among older adults (N = 3005). Based on spousal relationship literature using the NSHAP data, factor analysis was used to estimate factor scores conceptualizing two domains of relationship quality: relationship support (positive dimensions of relationship), and relationship strain (negative dimensions of the relationship). Logistic regression models were used to test the relationship between the relationship quality factor scores and the likelihood of each mistreatment type while controlling for gender, education, age, and race. Psychological abuse was more likely for older adults experiencing relationship strain with spouse , family , and/or friends . Financial abuse was more likely for those experiencing poor relationship support with family  and those experiencing relationship strain with friends . However, relationship quality was not correlated with likelihood of physical abuse. Interpersonal relationships with close others could provide stronger support and care, but relationship strain might contribute to mistreatment. When determining safeguarding gatekeepers to protect older adults from potential mistreatment, interventions should consider the quality and composition of interpersonal relationships with close others.


The study of threshold levels of heavy metals in soil is essential for the assessment and management of soil environmental quality. This study reviewed the influencing factors, the derivation, and application aspects of heavy metals’ threshold values comprehensively by a combination of bibliometric analysis and scientific knowledge mapping. A total of 1106 related studies were comprehensively extracted from the Web of Science database during the period from 2001 to 2020. The results showed that the publication output has been growing strongly. An analysis on the subject, journal, country, and institution was carried out to demonstrate the development and evolution of this research branch during the two decades. According to high-frequency keywords analysis, external factors  and internal factors  can affect heavy metal threshold values in the soil–crop system. The current methods mainly include the Point model , the Probability model , and the Empirical model . A threshold study can be applicable to the risk assessment for soil heavy metal contamination in order to determinate the soil pollution degree and its spatial and temporal distribution characteristics. Moreover, challenges and prospects of the study of heavy metal threshold values are proposed, indicating that research should focus on the relationships between human health risks and the established threshold values of heavy metals in the soil, long-term field trials and bioavailability of heavy metals for the derivation of the thresholds, and the establishment of more scientific and rational soil environmental benchmarks. Soil contamination has attracted widespread attention globally ,2,3. WitThreshold levels of heavy metals in soil re the maximum heavy metal concentrations that the soil can possess without destroying ecosystems . The derBibliometric analysis is a method to summarize historical achievements and development trends comprehensively, systematically, and objectively. It can also explore possible future research directions of the research field with the help of mathematics and statistics, computer analysis and information visualization technology, combined with the analysis of the literature ,18. ScieIn this study, a literature review was combined with a bibliometric analysis and scientific knowledge mapping to analyze studies on heavy metal threshold levels in soil published in the last two decades. The influence factors, derivation, and application aspects of the threshold levels were summarized through high-frequency keywords analysis. Moreover, the challenges and promising research frontiers of research on heavy metal thresholds are discussed.Publications were obtained from the online version of the database of Science Citation Index-Expanded (SCI-E) of the Web of Science (WoS) core collection. Records retrieval started with a topic search for “soil,” “heavy metal,” and “threshold” in the publication year range from 2001 to 2020. Some repeated or irrelevant records were removed after analyzing each record. Finally, a total of 1106 records which met the study requirements were obtained.CiteSpace, regarded as a useful, efficient scientific visualization tool, was used to analyze the related literature and construct scientific knowledge maps . It was As shown in Publications in the field of research of heavy metal thresholds in soil were distributed in 55 unique subject categories. The most productive discipline in this field was Environmental Sciences and Ecology, accounting for 67.18% of the studies (743 records), followed by Agriculture, Engineering, Water Resources, Toxicology, Geology, Public and Environmental Occupational Health, Chemistry, Plant Sciences, Science Technology, Other Topics, Geochemistry Geophysics, and Biodiversity Conservation .Science of the Total Environment was the journal with the highest number of citations, followed by Environmental Pollution, Chemosphere, and Journal of Hazardous Materials  . Top 50 Heavy metal pollution was often closely related to geogenic sources , mine waFrom 2001 to 2005, some studies focused on the toxic effects of heavy metals in soil on different crops to explore models and methods for derivation of the thresholds . For exaBased on threshold studies, risk assessment can determine a soil pollution degree and spatial and temporal distribution characteristics . It coulFrequency bursts can indicate that the scientific community has paid or is paying special attention to the contribution of specific factors, and burst detection can identify burst keywords as indicators of emerging trends . As showHeavy metals in soil can enter the food chain after enrichment in crops, which can pose a severe threat to human health. Moreover, human beings accumulate heavy metals also through inhalation of particles in soil and by dermal contact . Under tThe current studies mostly use short-term pot experiments or field trials to understand quantitative relationships regarding heavy metal concentrations in soil–crop systems. Large spatiotemporal differences in the experimental conditions between pot experiments and field trials often lead to inconsistent experimental results. Consequently, heavy metal thresholds in soil often failed to meet the requirements of soil pollution risk assessment, with relatively poor reliability. Determining quantitative relationships and studying the dynamic changes of heavy metal thresholds in long-term field trials may become future research topics.At present, methods for determining heavy metal thresholds in farmland soil mainly consider the total amount of heavy metals as evaluation standards. However, the total amount of heavy metals cannot fully represent the actual toxic effects on crops and humans. The pH, organic matter content, and other factors should be considered for the derivation of heavy metal thresholds, and this requires research innovations. Therefore, the construction of new derivation methods for thresholds based on the bioavailable state of heavy metals in the soil may be an important development direction.Soil environmental benchmarks based on heavy metal thresholds can scientifically reflect the risk of heavy metal contamination in soil on related receptors. They can guide the formulation of soil environmental quality standards and subsequent pollution risk assessment. However, the current soil environmental benchmarks in many countries are hard to meet; therefore, there is a need to scientifically formulate soil environmental quality standards. For example, heavy metal threshold values based on different pH levels and land-use types were established in the China’s current farmland soil environmental quality standard (GB15618-2018). This standard can be beneficial to determine different farmland soil pollution levels preliminarily. However, this standard did not take into account other factors influencing heavy metal thresholds, such as soil types, soil physical and chemical properties , and crop varieties. As a result, it may cause risk assessment results to deviate from reality, which can lead to “overprotection” or to “inadequate protection” in relation to soil environmental quality safety. Therefore, establishing more scientific and rational soil environmental benchmarks regarding heavy metal thresholds in soil may be important research direction.Based on a big data analysis of 1106 studies, the following results on heavy metal thresholds in soils were obtained: (1) Environmental Sciences and Ecology, Agriculture, and Engineering were the three main disciplines concerned with heavy metal threshold research. (2) Journals, countries and institutions with the highest number of articles published were identified, and the development and evolution of these studies during the two decades were demonstrated. (3) Systematical analysis of external influencing factors  and internal factors , of derivation methods , and of application aspects of heavy metal threshold studies from 2001 to 2020 was carried out. (4) Challenges and future prospects of heavy metal threshold studies were proposed, indicating that research should focus on the relationships between human health risks and the established thresholds of heavy metals in soil, the derivation of thresholds based on the bioavailability of heavy metals and long-term field trials, and the establishment of more scientific and rational soil environmental benchmarks.


The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division. The United States Food and Drug Administration (FDA) recently highlighted regulatory science as an Agency priority in its “2021: Advancing Regulatory Science at FDA: Focus Areas of Regulatory Science (FARS)” report . Locatedin silico research performed by informatics and computational modeling groups. In addition, DARS conducts clinical research focused on facilitating new and biosimilar/generic drug development and assessing the safety of marketed drugs. Using applied research, DARS investigates questions related to clinical pharmacology, medical toxicology, systems pharmacology, chemistry, and biology  and other examples involved the prescription drug, remdesivir, a treatment for COVID-19.Journal of the American Medical Association: JAMA , a probable human carcinogen, were detected in specific ranitidine products. Ranitidine products were removed from the US market in April 2020, owing to the unacceptable amounts of NDMA in ranitidine products. Additionally, the petitioner postulated that ranitidine could convert to NDMA in people. In response, DARS, working with FDA’s Office of New Drugs and Office of Pharmaceutical Quality, designed a rigorous clinical study that carefully controlled for factors known to influence NDMA exposure and measurements including diet  and to advance drug development tools for new opioid antagonists  methodology that uses molecular structure to predict the biological function  structure-activity relationship, or (Q)SAR, models has become an integral part of regulatory review as it can rapidly assess a compound’s toxicological and pharmacological properties based solely on chemical structure , 44. (Q)in vitro and in vivo methods to identify best practices when conducting transporter- or metabolism-based drug-drug interaction studies. For example, conflicting information appears in the scientific literature regarding the extent of specific cytochrome P450 (CYP) involvement in metabolizing methadone (a treatment for opiate dependence). Drawing from previously submitted new drug applications, DARS constructed a database of drug-drug interaction studies between methadone and antiviral medications known to affect these CYP enzymes  in humans to a proposed biosimilar or generic drug than that seen with the innovator product. For most biosimilars this is still assessed through clinical trials. DARS is studying the ability of non-clinical approaches to predict immunogenicity risk without conducting a clinical trial. This includes assessing specific Performing clinical studies in pediatric populations that involve frequent blood samples can be challenging if conventional methods are used that require relatively large blood volumes that can limit generic drug development for children. An alternative method is determining the concentration of drug in blood from dried blood spots (DBS) that only require 10 μl of blood compared to ∼5 mL (500 times more) with conventional methods. However, there has been a lack of analytical methodology metrics for using DBS analysis for generic drug bioequivalence studies. DARS developed and validated novel, sensitive, and specific analytical methods  to suppoin vivo study to evaluate an in silico modeling approach for delayed-release risperidone injectable products that might be used to inform clinical trials for generic drug approvals. Another recent study investigated slow-release dexamethasone intravitreal implants used to treat inflammatory conditions in a wide variety of ocular diseases. Unfortunately, no generic implants are available on the market largely due to the challenges associated with measuring drug concentration within the eye to establish bioequivalence. DARS conducted a non-clinical in vivo study to measure and correlate intraocular and systemic dexamethasone concentrations after intravitreal implantation  who have such rare variants that the patient population is too small for an adequately powered clinical trial. An in vitro cell-based approach was used to assess the response of the mutated or dysfunctional proteins in the presence of drug to make inferences about the potential for response in patients. As a result, the 2017 expanded approval of ivacaftor has allowed ∼1,500 new patients access to the drug based on in vitro data that predicted the clinical responsiveness of patients not included in clinical trials  variants is expected  may serve as a renewable source of differentiated cell types with patient- or population-specific properties –76. ThisPediatric cancers are rare diseases with limited treatment options . To faciAs a part of FDA’s mission to ensure the safety and efficacy of human drugs, FDA reviews drug developer submitted data to establish under what conditions a new drug can be safely administered to patients and whether the new drug carries an increased risk of various adverse effects. This involves assessing end points that cannot be ethically obtained in humans, such as histopathological analysis of all major organs. Animal studies have played a critical role to meet this need and bring safe and effective therapies to patients. At the same time, FDA has a long-standing commitment to replace, reduce, and refine animal testing (the “3Rs”) with successes to date in harmonizing regulatory guidelines with international regulators and accepting alternatives to animal testing in certain areas , 79. Recin vitro models, including with iPSCs and microphysiological systems, to fill information gaps about the potential utility of these assays for regulatory contexts of use and to assess reproducibility, quality control and performance criteria. This has included studies on liver microphysiological systems  initiative was implemented by FDA in collaboration with public-private partnerships including industry, academics, and other global regulators .–87.in vi•in vitro ion channel assay standards, best practices, and variability  in developing new Questions and Answers (Q and As) to the ICH E14/S7B “Clinical and Non-clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential” guideline . This neThe growing use of (Q)SAR models for the safety assessment of drug products led to the formation of the DARS Computational Toxicology Consultation Service . DARS stThe ICH M7(R1) international regulatory guideline recommends the use of (Q)SAR predictions as a state-of-the-art alternative to experimental testing to qualify a drug impurity for mutagenic potential . DARS reExtractable/leachable compounds are industrial chemicals that may be present in a drug product from manufacturing, packaging, drug delivery, and/or container closure systems. For non-mutagenic compounds with limited general toxicity data, a manual structure-activity relationship, or “read-across,” assessment based on structurally similar surrogate compounds may be used to inform setting a permissible daily exposure limit. DARS staff review applicants’ proposed surrogates for extractable/leachable compounds and, if needed, recommend alternative surrogates based on structural, metabolic, and physicochemical considerations.Nitrosamine impurities constitute a special class of potentially mutagenic impurities that are controlled to very low levels because of their high carcinogenic potency. Due to the limited availability of experimental data for these impurities, read-across and (Q)SAR models may be used to inform an acceptable intake based on structurally related surrogate compounds. DARS staff conduct read-across and (Q)SAR analyses and review structure-based justifications for proposed nitrosamine limits to support internal decision-making.The research topics and projects selected for this article represent only a part of DARS’ research portfolio and the Division’s work covers the full spectrum of regulatory science. To help further illustrate the breadth and depth of DARS’ work, this section highlights an additional sampling of projects.Within drug labeling, the overdosage section describes the signs, symptoms, and laboratory abnormalities that occur with drug overdose as well as recommendations on treatment, if known . AlthougAntimicrobial resistance (AMR) remains a significant global public health threat. FDA, in collaboration with internal stakeholders, develops approaches to detect, prevent, and limit the impact of AMR . In partAs mentioned previously, DARS comprises scientific thought leaders with decades of cumulative experience across the translational research spectrum. With their expertise, DARS staff not only lead cutting-edge research projects, but also lead or participate in multiple working groups and task forces. These in turn lead to the development of or significant changes to regulatory policies, decisions, and regulatory guidance. Below are examples.Division of Applied Regulatory Science generates data and evidence to help the Agency make the most well-informed regulatory decisions and take the most appropriate regulatory actions. Examples include issuing Drug Safety Communications, drug approvals, and as in this case, updating drug labeling. In 2018, information emerged showing a disproportionate number of neural tube defects in infants born in an HIV patient population treated with dolutegravir as part of a clinical trial . Over tiin vitro models in support of biomarker qualification and the new Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program. DARS is also leading the development of an evidentiary framework to advance the use of PD biomarkers for biosimilars. The draft version of this evidentiary framework was presented at a DARS-led public workshop  the Division’s laboratory, computational, and clinical research expertise, and infrastructure position it to be able to respond to the next challenges the Agency faces. In addition, DARS continues to help make drug development more efficient, as it has done with advancing new methods for biosimilar and complex generic drug evaluations and adopting new technologies to speed the development of treatments for rare diseases. Performing these mission-critical tasks involves complex science, innovative thinking, and a high-level of dedication.KC, RRa, RRo, and DS contributed to the development and design of the manuscript. KC and RRa wrote the first draft of the manuscript. All authors wrote sections of the manuscript, contributed to manuscript revision, read, and approved the submitted version.


Nowadays, with the rapid development of industry and agriculture, heavy metal pollution is becoming more and more serious, mainly deriving from natural and man-made sources ,2,3. NatThe remediation methods of heavy metal-contaminated soil mainly include physical remediation, chemical remediation and biological remediation . PhysicaIn recent years, phytoremediation has been widely studied as an economic, effective and green technology. Phytoremediation has become a research hotspot since Chaney et al. proposed using hyperaccumulative plants to restore heavy metal-contaminated soil ,44. PhytThe efficiency of the phytoremediation of heavy metal-contaminated soil mainly depends on plant biomass and its ability to accumulate heavy metals ,62. HoweSoil heavy metal pollution is a major problem worldwide. Compared with physical and chemical remediation methods, phytoremediation is a mild, relatively cheap and ecologically safe technology with huge potential. Looking forward, the following points deserve more attention: (1) Using molecular biology and transgenic engineering technology, we should screen and cultivate local genetic engineering bacteria and genetic engineering plants under heavy metal stress, and transfer target functional genes to plants, so as to improve the relevant remediation capacity of heavy metal-contaminated environments and reduce the disturbance to the contaminated soil ecosystem. (2) There is little concern about the remediation of heavy metal-contaminated soil under organic compound pollution, and the phytoremediation technology of organic–inorganic compound pollutants will be a hotspot in the future. (3) We need to find more efficient and safer microbial plants, chemical plants and other joint remediation technologies. (4) More and more attention will be given to the woody plant remediation technology with large biomass, great economic value and environmental value. (5) The application of artificial intelligence and machine learning for the environment will be more and more prevalent. Artificial intelligence and machine learning have huge application prospects in the research of heavy metal pollution remediation through plants, gene improvement and site remediation. (6) In future research, the medium scale remediation test of actual heavy metal pollution should carry out site construction to accelerate the transition of phytoremediation technology from a simulation experiment to practical application.This Special Issue was created to promote researchers in this field, presenting their thoughts, ideas, and discoveries of phytoremediation in environmental applications. Thank you to everyone who wants to or can contribute to this Special Issue.


The purpose of this project was to decrease the prescribing of benzodiazepines and sedative hypnotics in post-operative older adults.Routine prescribing of benzodiazepines and sedative hypnotics as first line choices for sleep medication is a known contributor to prolonged hospital stays, increased fall rates, increased development of delirium, higher health care costs, and long-term cognitive decline. Methodology: Practice changes included monthly provider and nursing staff education inservices, coupled with transparent monitoring of provider prescribing practices. The outcomes measure was to decrease the prescribing of benzodiazepines and sedative hypnotics by 5% within 90 days and increase the prescribing of melatonin by 10%.When comparing six months of data pre and post implementation on the unit, there was a 33% decrease in the prescribing of benzodiazepines/sedative hypnotics and a 12% increase in the prescribing of Melatonin. There was also a 28% decrease in the hours of patient safety sitter use, a marker for delirium. Implications: This quality improvement project decreased the number of benzodiazepines and sedative-hypnotics prescribed by expanding provider and nursing knowledge, which ultimately led to fewer hours spent utilizing patient safety sitters, thereby lowering healthcare costs, while concurrently improving the quality of care delivered


Myxobacteria are excellent model organisms for investigation of predator–prey interactions and predatory shaping of microbial communities. This review covers interdisciplinary topics related to myxobacterial predation and provides current concepts and challenges for determining predatory performance. Discussed topics include the role of specialized metabolites during predation, genetic determinants for predatory performance, challenges associated with methodological differences, discrepancies between sequenced and environmental myxobacteria, and factors that influence predation. Bdellovibrio bacteriovorus, which invade prey cells individually, myxobacteria are social predators capable of extracellular lysis of prey and subsequent swarming to claim released biomacromolecules for nutrition -glucanases, and proteases are likely involved in the predation of phytopathogenic fungi , Chondromyces apiculatus DSM436T (NZ_ASRX00000000.1), Chondromyces crocatus DSM14606T (NZ_CP012159.1), Labilithrix luteola DSM27648T (NZ_CP012333.1), and Sandaracinus amylolyticus DSM53668T (NZ_CP011125.1). Similarly low abundances of myxobacteria from frequently sequenced genera have been reported from several biogeographical studies  and Gram-positive (Micrococcus luteus) bacteria as well as Saccharomyces cerevisiae  and the National Institute of General Medical Sciences of the National Institutes of Health (P20GM130460).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.


Antimicrobial resistance is a public health emergency and represents an impending pandemic. Implementing the lessons learned from responding to the COVID-19 pandemic is essential in accelerating the development of new antimicrobials and therapeutic strategies, rapid diagnostics and improved vaccines. A rededicated, coordinated and collaborative global effort of all stakeholders in academia, healthcare, government agencies, industry, finance and philanthropy is essential to halt the continued spread of antimicrobial resistance and to prevent further morbidity and mortality from drug-resistant pathogens. This staggering statistic included 1.27 million deaths directly attributed to bacterial AMR. These estimates suggest that bacterial AMR caused more deaths in that year than those resulting from HIV/AIDS and malaria combined. The major burden of AMR deaths is reported in low-resource areas—those with limited healthcare systems, laboratory infrastructure, sanitation, clean water and antibiotic stewardship.2 In the US, the CDC reports that there are more than 2.8 million antibiotic-resistant infections and greater than 35 000 deaths associated with AMR each year.3 A coordinated, global effort is needed to halt the continued spread of AMR and the resulting morbidity and mortality from drug-resistant pathogens. This Call to Action requires increased support for biomedical research, as well as significant expansion of and incentives for new and improved diagnostics, antimicrobials and vaccine candidates in the medical diagnostic and pharmaceutical pipelines, respectively.Antimicrobial resistance (AMR) represents an ongoing public health emergency and an impending pandemic of overwhelming proportions. The WHO has declared AMR among the 10 worldwide public health threats facing humanity.4 The COVID-19 pandemic has underscored the critical role of biomedical research and development in responding to public health emergencies with accurate, easy-to-use and rapid medical diagnostics, safe and effective vaccines and therapeutics, as well as public–private partnerships resulting in the essential infrastructure for community engagement in clinical trials and uptake of medical countermeasures.5 We need to build on these hard-learned lessons from responding to the COVID-19 pandemic and rapidly apply them to improving the response to the AMR global health crisis. Now is the time to halt the continued spread of AMR by advancing novel and innovative strategies for: improved surveillance of drug-resistant pathogens; discovery, preclinical and clinical evaluation of safe and effective antimicrobials and other therapeutics; development and validation of diagnostics capable of rapidly identifying drug-resistant pathogens and differentiating between bacterial and viral infections; identifying and testing preventive interventions including safe and effective vaccines; investigating and developing strategies utilizing bacteriophage therapy; combining genomic sequencing with artificial intelligence/machine learning tools, as well as educating healthcare providers and the public on the urgent need to increase antibiotic stewardship.During the past 2.5 years, the ongoing COVID-19 pandemic has served to further accelerate the AMR public health crisis with the increased use of antibiotics in the treatment of patients with SARS-CoV-2, the virus that causes COVID-19, as well as resulted in major disruptions in healthcare systems and infectious disease monitoring and treatment.6 As of late 2021, there were 77 antibiotic or combination agents and 217 antibacterial candidates in the clinical and preclinical development pipelines, respectively, targeting the 13 WHO priority pathogens, including Mycobacterium tuberculosis and Clostridioides difficile.6 The limited number of potential antimicrobials in these pipelines are inadequate to counter the rapid spread of AMR, as well as the continual occurrence of drug resistance and broad-spectrum AMR demonstrated by many pathogens.2The development of antimicrobials is an essential step in addressing the AMR crisis; however, from 2017 to 2022 only 12 new antibiotics have been approved by the US FDA and/or the EMA. The majority of these newly approved antibiotics demonstrate limited clinical benefit over existing treatments and approximately 80% of these drugs are from existing classes of antibiotics where mechanisms of resistance have previously been demonstrated.7 The NIH and the Biomedical Advanced Research and Development Authority (BARDA) AMR Diagnostic Challenge awarded 20 million USD to support innovative, accurate, rapid, point-of-need medical diagnostic tests to detect drug-resistant pathogens or differentiate between bacterial and viral infections.8 Additionally, public agencies  and private foundations and organizations worldwide are supporting key biomedical research that provides the basis for identifying new targets for antimicrobial agents, repurposing existing drugs, vaccines and other countermeasures to combat AMR. The UK and Sweden initially launched pilot subscription-based models to ensure pharmaceutical manufacturers of guaranteed contracts irrespective of the actual number of antibiotics sold. Based on the pilot program in the UK, the NHS has recently implemented the ‘Netflix’ subscription-style payment programme for two antibiotics, including cefiderocol and ceftazidime with avibactam.9 In the US, two congressional bills have been recently drafted, including the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act and the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act, to stimulate the Federal Government’s and industry’s development and use of novel antimicrobial agents.10 At this time, only the PASTEUR Act is continuing to progress toward authorization.11During the past several years, numerous targeted initiatives have been launched to increase the number of antimicrobials and other strategies to counter AMR across different stages of the pipeline from basic biomedical research through to clinical trials and regulatory approval. These ongoing activities have included the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator , the Antimicrobial Resistance Multi-Partner Trust Fund , the Global Antibiotic Research & Development Partnership , the Replenishing and Enabling the Pipeline for Anti-Infective Resistance Impact Fund (estimated at 125 million USD) and the AMR Action Fund . Most recently, the AMR Action Fund has awarded funds to two companies with novel approaches utilizing bacteriophages or β-lactam/β-lactamase inhibitors.All of these programmes are highly commendable; however, more must be done now to fill the discovery and development pipelines and ultimately, pharmacists’ shelves, with the crucial antimicrobials, including oral and paediatric formulations, that are urgently needed. Our collective fight against AMR requires a reinvigorated, rededicated, coordinated and collaborative dedicated effort to accelerate the development of innovative and improved strategies to prevent, treat and diagnose AMR. Additional public and private funds are essential to support: continued biomedical research to identify new lead compounds and drug targets; strategies to de-risk pharmaceutical and biotech companies to fill the diagnostics, drug and vaccine pipelines; legislative and governmental incentives to encourage development of new and improved antimicrobials; and education of healthcare providers and the public on the need for antibiotic stewardship. This Call to Action requires that all of us—members of the pharmaceutical, biotechnology and medical diagnostic industries, along with healthcare providers, researchers in academia and government agencies, regulators, lawmakers, private investors and philanthropy communities join together to end the AMR crisis before it becomes an even greater public health emergency than the COVID-19 pandemic. Only through strategic and collective activities, at both the individual and global population level, can we hope to halt the further spread of AMR. These efforts targeting AMR must be a crucial component of our comprehensive plans and policies for pandemic preparedness and response. FasterCures and the Milken Institute stand ready to work with our public and private partners to stop AMR and prevent the impending AMR public health pandemic.


The global COVID pandemic has highlighted the need for the reporting of enhanced serology data from laboratory testing data. Qualitative results alone do not provide detailed data to understand levels of SARS-CoV-2 seroprevalence within a populace. To enable this, a minimum data set is required to support standardised data reporting.The CO-CONNECT project is concerned with the response to COVID within the UK and how datasets can be made Findable, Accessible, Interoperable and Reusable (FAIR). One aspect of this is a focus upon improving granular levels of COVID serology testing data being reported by national laboratories to the National Pathology Exchange (NPEx). A study was conducted to ascertain the essential data elements that could formulate a COVID Serology Data Standard (CSDS). Three NHS laboratories acting as pilot studies and NPEx have been actively involved with the development of the CSDS, together with clinicians and academics from the CO-CONNECT project.Feedback from clinicians, academics and NPEx has been collected, together with NHS laboratory feasibility analysis to derive a minimum set of data elements that form a proposed data standard to standardise the reporting of laboratory COVID serology data for the UK. The proposed CSDS comprises twelve data elements in total, grouped into four main areas, (1) subject identifier and test date and time, (2) analyser types, test kits and samples, (3) qualitative results and (4) quantitative results. To further support the standardisation effort, a proposed Health Level Seven (HL7) message structure has been created to enable the reporting of the CSDS data elements to NPEx.The CSDS has been created to help augment levels of reported granular data for laboratory COVID serology testing. If adopted, this could enable healthcare professionals to better understand the calibration of assays across multiple analyser types and thus antibody response levels.