Spatial transcriptomics, the technology of visualizing cellular gene expression landscape in a cells native tissue location, has emerged as a powerful tool that allows us to address scientific questions that were elusive just a few years ago. This technological advance is a decisive jump in the technological evolution that is revolutionizing studies of tissue structure and function in health and disease through the introduction of an entirely new dimension of data, spatial context. Perhaps the organ within the body that relies most on spatial organization is the brain. The central nervous system’s complex microenvironmental and spatial architecture is tightly regulated during development, is maintained in health, and is detrimental when disturbed by pathologies. This inherent spatial complexity of the central nervous system makes it an exciting organ to study using spatial transcriptomics for pathologies primarily affecting the brain, of which Glioblastoma is one of the worst. Glioblastoma is a hyper-aggressive, incurable, neoplasm and has been hypothesized to not only integrate into the spatial architecture of the surrounding brain, but also possess an architecture of its own that might be actively remodeling the surrounding brain. In this review we will examine the current landscape of spatial transcriptomics in glioblastoma, outline novel findings emerging from the rising use of spatial transcriptomics, and discuss future directions and ultimate clinical/translational avenues. Developmental patterning, the process of determination of final fate and ultimate locations for all cells originating from the initial cluster of stem cells in a developing embryo, is essential for normal development of a multicellular organism. A chief driving factor behind developmental patterning is cellular location and exposure to gradient signaling cascades such as SHH and WNT pathway signaling –6. FurthUnderstanding cellular behavior in its native location and organ system is fundamental to not only basic developmental biology but also to defining a pathological condition and developing relevant therapeutics. Since the development of mRNA analysis techniques, our understanding of diseases such as cancers have evolved exponentially. By analyzing the overall gene expression profile of the cancer cells, it was not only possible to better define the disease and its behavior, but it has also led to development of several targeted therapies that greatly increased the chance of survival for cancer patients , 15. HowExperimentally, the most reliable forms of gene expression analysis have relied on tissue dissociation and even with the advent of single cell sequencing, barcoding for cells has only been able to track cell types, not their original position within their tissue of residence. Dissociation of tissue, especially with complex spatial organization such as the brain, induces cellular stress and exposes cells to foreign environments which impacts the overall transcriptional profile and ultimate results of the experiments –18. EvenA pathological condition where the tissue microenvironment plays a curial role in disease progression and therapeutic resistance is glioblastoma (GBM). GBM is the most common primary brain cancer in adults, with limited prognosis and strong resistance to all current therapies –21. Multin-situ hybridization (FISH) have been utilized to study microenvironmental heterogeneity and conduct crude spatial profiling (through location specific biopsy sampling throughout tumors (in-situ hybridization) of biopsy resections from the leading edge, infiltrating tumor, cellular tumor, pseudopalisading cells, and microvascular proliferation  within t tumors –40. The feration . The datferation . Across feration . Althoug experiment starts from a tissue section frozen and sliced to preserve the tissue spatial architecture. While many techniques are available for profiling gene expression spatially across a tissue, the most widely used are the commercial platforms Visium (from 10x Genomics) and GeoMx (from Nanostring) . Each ofin-situ hybridization techniques. These images are used for manually selecting regions for expression profiling. These so-called regions of interest (ROIs) are selectively exposed to UV light which cleaves the oligonucleotide tags from the probes or antibodies bound to their targets within the selected regions. The cleaved oligonucleotide tags are then collected and hybridized to a complementary barcode array which is subsequently read by a fluorescence scanner to produce digital counts for each target within the ROIs; alternatively, the cleaved tags can be prepared for sequencing. In either case, the GeoMx technology provides the high-resolution images used to select the ROIs along with count data (or sequenced reads) at each ROI  , 45. SpaSequenced reads can be aligned to a reference transcriptome using any of several alignment tools. Due to its relatively high accuracy, low biases, and speed, STAR is a widely used approach in ST experiments and the default approach implemented is SpaceRanger (10x Genomics Space Ranger 2.0.1). To ensure the accuracy and reliability of the data, it is important to perform quality control following alignment. SpaceRanger provides sequencing and spot-specific metrics to diagnose sequence and spot quality. Given that Visium provides fastq files, most metrics provided in SpaceRanger are the same as those used in fastqc for quality control of bulk or single-cell RNA-seq data. Specifically, percentage of valid barcodes, percentage of valid UMIs, and sequencing saturation metrics are provided and can be used to identify overall sequencing quality; mean reads per spot, median UMI counts per spot, and percentage of genes detected may be used to filter out low-quality spots. The fraction of reads in spots under the tissue is specific to ST experiments and provides a measure of reads with tissue-associated barcodes. Low fraction reads may indicate that many of the reads were not assigned to tissue covered spots due to high levels of ambient RNA, or poor tissue orientation. Finally, spot-swapping is present in most experiments (spot-swapping occurs when reads from a given tissue spot bind probes at a nearby spot) and should be adjusted for using SpotClean .Following alignment and quality control, normalization is often performed to adjust for differences in expression levels that result from technical artifacts so that expression may be compared within or between samples. As discussed in , many syFollowing normalization, clustering is often done to identify cell subtypes followed by characterization either by identifying marker genes that are highly expressed in the cluster, or those highly expressed relative to other clusters via differential expression (DE) analysis. While the H&E stain (or related image) provides much insight into cell subtypes, molecular determination of subtypes can lead to refined characterizations.Methods for clustering and identification of DE genes that were widely used for scRNA-seq continue to be used in ST data analysis. These include k-means and graph-based methods such as Louvain, and Leiden for clustering; and the Wilcoxon rank-sum test and DESeq for identification of DE genes. These latter DE methods do not appropriately accommodate replication at the cell and sample level, and, because of this, pseudo-bulk approaches have been recommended . UnfortuIn summary, the methods most used for analysis of ST data were initially developed for bulk or scRNA-seq. A typical workflow for Visium data uses SpaceRanger for alignment using the default method STAR; data are then often imported into Seurat for normalization, clustering, and DE analysis via the default methods scran, k-means on UMAP principal components, and the Wilcoxon rank-sum test, respectively. GeoMx provides a similar pipeline with STAR for alignment followed by estimating gene expression levels, filtering, normalization, and further analysis. As discussed above, many methods have been developed specifically for ST data that improve upon the basic methods implemented in SpaceRanger and GeoMxTools. Most were developed for Visium data with applications to GeoMx data possible, with the caveat that some methods require contiguous spots which are not available in GeoMx. In addition, there may be technical artifacts in GeoMx data that are not accommodated by common statistical assumptions and new methods are required .Intratumoral heterogeneity of the GBM tumor microenvironment (TME) is the difference in genetic, molecular, and physical structures of the tumor cells, and their native cell counterparts, all present within the native tumor microenvironment , 71. BecAs sequencing technology advanced and single cell RNA seq (scRNAseq) was developed further interrogation of GBM tumor samples uncovered more complex “hybrid” states at the single cell level. In these states bulk tumors were found to consist of heterogeneous mixtures of individual cells corresponding to different GBM subtypes, rather than every cell within a tumor being a consistent subtype . This fiWithin the GBM TME there are also a myriad of complex cell types that makeup the surrounding normal brain tissue as well as the patrolling and invading lymphocytes attempting to respond to tumor growth. These cell types include but are not limited to microglia, neurons, macrophages, T-cells, MDSC’s, astrocytes, and oligodendrocytes , 73, 76.Although scRNAseq is a clear advancement over bulk RNAseq in furthering our understanding of GBM heterogeneity and has significantly added to the identification of potential therapeutic molecular targets, it is still limited in its ability to capture cellular behavior in its native ecosystem. Furthermore, FISH can provide true spatial gene expression information but due to the limitations of multiplexing is only available for a small number of targets. The culmination of all this research gives a glimpse of how complex both GBM and its TME are, however, until the advent spatial transcriptomics a final piece of the puzzle remained missing.Initiatives such as Ivy Gap have made significant contributions to understanding glioblastoma and its complex microenvironment, however, its limited sample size along with the need for sample dissociation prior to sequencing are critical limitations. These limitations make clear the need for a sequencing method that can take spatial location into account and allowing for a more complete picture of GBM TME and its interaction with the surrounding tissue microenvironment.Recent work involving both single cell and spatial methodologies is just beginning to highlight novel and promising discoveries . The autRavi et al. conducted a similar study using 12 patient tumor samples but this time focusing less on the tumor spatial structure and more on the structure of the TME, and specifically the tumor surrounding T-cells . They deRen and colleagues examined both diffuse midline glioma as well as GBM using spatial transcriptomics and note that both tumor types display niche specific microenvironments and transcriptional programs . Specifiin vivo and in vitro controlled experimentation is needed.Taken together, these early studies conducted thus far using spatial transcriptomics on GBM and other high grade brain tumors definitively show that there are region specific and distinct gene expression programs throughout the tumors. These programs display similar amounts of intertumoral heterogeneity as was hypothesized when bulk and single cell sequencing studies were conducted in GBM, however, in some of the larger sample studies, patient specific variations can be observed such as the hypoxic niche and proliferative edge programs . CriticaThe most challenging aspect of any new research technology is its eventual integration into the clinic to try to better patient outcomes. GBM represents a disorder desperately in need of new therapeutic developments ranging from prognostic biomarker discovery to novel interventions aimed at prolonging survival. To successfully translate new discoveries into clinic the barriers of efficacy and safety, which are much higher than the common basic science barrier of statistical significance, must be surpassed. This translational step is where many of the current bioinformatic advances in GBM have fallen short. For example, studies have demonstrated repeatedly that specific molecular subtypes exist within patients , 38, 75,An avenue of clinical research that could directly benefit from spatial transcriptomics is the integration between GBM and cells that make up its TME. A novel player in the GBM/TME interactions is surrounding neurons. New evidence supports a key role played by neuron cells in glioma’s TME through the existence of neural-glioma networks –83. ThesAnother avenue for spatial transcriptomics to make clinical inroads is in discovery of novel biomarkers of disease progression. Biomarkers of response to standard of care in gliomas remain extremely limited, with MGMT promoter methylation and IDH mutation status as the only predictive biomarkers currently in clinical use in malignant gliomas . This deThe effects of different therapeutics on GBM and its TME can also be more fully taken into consideration using spatial transcriptomics. The gold standard chemotherapy for GBM is temozolomide (TMZ), however, the impact of temozolomide in the TME modulation remains unclear, with some reports suggesting its potential use as an enhancer of immune activation in regimens combining TMZ with immunotherapy , whilst Immunotherapy represents another example of the importance of the TME and tumor-TME interactions. In GBM, multiple approaches have been attempted and continue to be proposed, including CAR-Ts , 109–111Across the clinical landscape of GBM there are a wealth of opportunities to leverage spatial transcriptomic data to create more specific and accurate predictors of response. A change in the design of upcoming clinical trials can also consider the spatial transcriptomic landscape of tumors from patients on the study offering personalized medicine specific therapies based on the profile of an individual patient’s tumor. These more spatially centric basic science studies and clinical trials can further improve the discovery of novel effective drugs and patient responders (Advances in spatial transcriptomics may hold the key to unraveling the highly nuanced biology behind all manner of complex processes from development to disease. As further technological advances are made within the field, integration of proteomic data with spatial location seems to be a crucial next point of exploration . FurtherWithin the landscape of disease, the greatest challenge will be drawing not only biologically meaningful but clinically meaningful conclusions and data from these experiments. Current research further characterizing the subtypes of GBM have yielded little clinical results thus far, perhaps the combination of spatial data from both the TME and native tissue microenvironment can enable discovery of targeted treatments. New directions for spatial sequencing experiments in GBM can begin to explore more in-depth tumor-neuronal interactions which have already been documented in the literature –83. Direin vitro organoid modeling of things such as vascular development, or the growth of tumors from an early seeding stage. Although this could be somewhat crudely done currently with just serial spatially profiled experiments, technological advances in microscopy and sequencing that would allow for continuous profiling of a single specimen could be revolutionary. Additionally, with serial spatial experiments, as well as the development of technologies that can label cell interactions such as RABID seq (Finally, the last critical dimension of sequencing that has eluded the biological and bioinformatics community is time. Over time spatial architecture changes and interactions between cells are formed and broken, with the power to now see these interactions in their native spatial landscape revolutionary discoveries stand to be made both in normal and disease models. This type of technological advance would be well suited for fields such as embryology or brain development where expression changes over time drive vast cellular architectural changes. These experiments could also be utilized for ABID seq , authentTo truly make meaningful gains in patient survival in a disease as devastating as GBM researchers need to make use of all the tools at their disposal. Spatial transcriptomics represents a worthwhile tool added to the investigator arsenal, however, our tools are only as good as the questions we use them on. As our methods evolve so too must our hypotheses in order to fully realize our ultimate goal of ending GBM.JS: Writing – original draft, Writing – review & editing, Conceptualization, Project administration, Visualization. LC: Writing – original draft. AG: Writing – original draft. DG: Writing – original draft. SP: Visualization, Writing – review & editing. AQ-H: Supervision, Writing – review & editing. CK: Supervision, Writing – review & editing. MD: Supervision, Writing – original draft, Writing – review & editing.


One of the primary goals of educational research is to identify effective and equitable school practices that aim to promote desired educational outcomes for all students, regardless of their background. This pursuit raises the question of why certain countries or schools demonstrate more favourable outcomes than others. To shed light on this question, this special issue delves into the Nordic countries  as a showcase.Despite their similar historical, cultural, and economic characteristics, these countries show vastly different levels of student outcomes. This special issue comprises seven studies that utilize data from the international large-scale assessments , leveraging their international comparative design and nationally representative student samples. The present article provides an overview of the seven included studies by underlining the key themes that transcend them as well as their contributions and implications. These themes include the measurement of educational effectiveness with international large-scale assessments, the central role of teachers, and the importance of both cognitive and non-cognitive student outcomes in studying different perspectives on effective and equitable school practices. What makes a school practice effective and equitable for all students? The answer to this question is the Holy Grail of educational research. Researchers have long sought to find out how different aspects of school systems—including teacher competence, school characteristics, and educational policies—can be optimized to provide excellent learning opportunities for diverse groups of students  as a showcase because these countries have very similar historical, cultural, and economic characteristics, which implies that schools and teachers work under somewhat comparable conditions. Despite these commonalities, the Nordic countries show very different results in the large-scale assessments across subject areas and trends over time.As Fig. The heterogeneity of the results across the Nordic countries Fig.  indicateThe seven studies included in this special issue add to the existing body of research by examining various factors that contribute to effective and equitable school practices. The implications of these findings are relevant for policymakers, stakeholders, and practitioners in education in their efforts towards improving educational outcomes and promoting equity in education. Table Steinmann and Olsen  proposedSiebecke and Jarl  used PISRohatgi et al.  examinedNilsen et al.’s  study aiYang Hansen et al.  addresseIn their study using PIRLS 2016 data, Leino et al.  identifiCosta and Chen  analysedThis special issue features seven articles that explore different perspectives on effective and equitable school practices using Nordic countries as examples. Steinmann and Olsen  highlighWhile the Nordic countries differ in mean achievement levels and trends over time see Fig. , there aAnother recurring finding in this special issue is related to the importance of considering students’ non-cognitive outcomes, such as self-concept, motivation, and attitude, in promoting educational equity (Leino et al., As in any analyses using international large-scale assessment data, the studies in this special issue also encountered a common limitation related to the cross-sectional design of the data, which hinders the tracking of changes at the student level over time and establishing cause-and-effect relationships. To address this limitation, TIMSS Longitudinal study — an extension of the traditional TIMSS 2023 assessment — offers promise by following the same cohort of students over time. This study allows to track changes at the student level and to draw more robust causal inferences about student learning. However, it should be noted that only Sweden decided to participate in TIMSS Longitudinal, which highlights the need for other Nordic countries to participate as well. Another potential avenue for causal inference from the international large-scale assessments is to extend the TIMSS international design by assessing two grades per school instead of one. As demonstrated in Steinmann and Olsen’s  study, tIn today’s world, where the COVID-19 pandemic, war, and energy crises have exacerbated educational inequalities, understanding effective and equitable school practices is more crucial than ever. Thus, special issues like the present one offer valuable insights to policymakers and educational stakeholders seeking to address these challenges. By prioritizing effective and equitable school practices, we can ensure that all students have access to high-quality education, regardless of their background and circumstances, particularly during these challenging times.


Current evidence indicates that elite-level coaches encounter a range of performance, organizational, and personal stressors that may influence or compromise mental health. With exposure to these stressors, supports need to be established to protect and preserve the mental health of elite-level coaches. Given the paucity of evidence available, this article proposes a number of considerations that should be taken into account when developing a mental health and rehabilitation framework for high-performance coaches. We argue that early intervention should be positioned at the core of this framework, to address the onset of symptoms prior to the emergence of a mental disorder or mental health crisis. Mental health screening and monitoring of coaches, the psychological safety of high-performance environments, the mental health literacy of coaches, and the tailored pathways to support are discussed. Beyond these strategies, it is proposed that rehabilitation and reintegration should be addressed to assist coaches who are currently experiencing mental ill health or have left their role due to mental health reasons. Although further research is needed to implement evidence-based strategies, it is recommended that a future mental health framework should incorporate the perspectives of coaches to ensure it is consistent with their needs and experiences. Conversely, those with a diagnosed mental disorder could potentially experience high levels of well-being throughout their day-to-day lives. Keyes’ model is beneficial to researchers and practitioners because it provides a conceptual framework that can be used to categorize and distinguish between an individual experiencing low well-being or mental ill health (or both). Since research indicates that individuals who “languish” for prolonged periods are more susceptible to developing mental disorders over time,,,,,,,,,,,,,,,,,,Despite scant research to date, preliminary evidence suggests that elite-level coaches are potentially vulnerable to a range of mental disorders. Findings indicate that high-performance coaches experience symptoms associated with depression,,,One of the most effective ways to provide timely support to coaches is through early intervention. This strategy has been recommended by researchers for both elite and youth elite athletes.In an elite sports context, Purcell and colleagues,To identify coaches who may be at risk or currently experiencing a mental disorder, screening tools are an effective measure that can be employed to detect symptoms associated with mental ill health. In 2021, the International Olympic Committee developed the Sport Mental Health Assessment Tool 1 (SMHAT-1) and Sport Mental Health Recognition Tool 1 (SMHRT-1) to examine symptoms of mental ill health in elite athletes.,Given the current sensitivity of disclosing mental health concerns in high-performance sport, screening processes should be ethically managed, ideally by qualified mental health practitioners or sports medicine physicians.During the screening process, it is vital that timing is taken into consideration when assessing the mental health of high-performance coaches. Although screening can be delivered during standard competitive periods ,,The beliefs and attitudes about mental health can play a pivotal role in early identification and responses to the initial onset of symptoms.,,Although interventions have been developed to enhance the mental health literacy of coaches,Though initially developed as a construct outside of sport, over recent years psychological safety has garnered increased attention in sporting contexts.Given that psychologically safe climates might empower individuals to disclose mental health problems and pursue mental health services, an early intervention framework should also consider the environmental supports that could be established to protect the mental health of elite-level coaches. Recently, Rice and colleagues,,,,When developing a mental health framework for high-performance coaches, pathways to mental health supports should also be considered. Coaches are prone to symptoms associated with stress and burnout,Australian Institute of Sport,Despite the presence of stigma, there may be contexts in which elite-level coaches seek to engage with psychological services.prevent experiences of mental ill health. Coaches—like other members of the community—will be susceptible to episodes of psychological distress from general life adversity , in addition to work-related challenges and setbacks. Evidence-based psychological and pharmacological treatments exist for a range of mental disorders,,,,,Although it is critical to intervene at the earliest opportunity when symptoms of mental ill health arise, it is neither realistic nor appropriate to completely Since Keyes’ model asserts that an individual can flourish  despite the diagnosis of a mental disorder, we argue that sporting organizations must prioritize support and early intervention over dismissal or prolonged stand-downs for coaches experiencing an episode of mental ill health. This support is paramount if the high-performance sports industry wishes to maintain the best-in-class coaches. If elite-level coaches are fearful or apprehensive about the implications of a mental health crisis or disorder, stigma will continue to persist, and the desirability of the role may decrease, given there may be more stable, supportive, and appealing opportunities elsewhere. To ensure high-quality leaders stay within the industry, coaches need to feel supported by their relevant organizations or federations, rather than isolated or detached.,,,,,For elite-level coaches who experience mental ill health, some individuals may feel it necessary to depart from the role.There is growing recognition that elite-level coaches, who operate in the same high-performance and outcome-focused environments as athletes, might also be susceptible to the same mental health difficulties their athletes face. Empirical research evaluating the mental health of elite-level coaches, however, is still in its infancy. This article has subsequently proposed a range of factors that should be considered when developing a framework to support the mental health of elite-level coaches . Althoug,,To develop a mental health framework that could provide coaches, practitioners and organizations with a set of guidelines to manage coach mental health, researchers need to better understand how elite-level coaches experience mental health. Researchers should also investigate theory-based strategies and interventions that could be employed to protect coaches from mental ill health .Beyond the contents of a framework, timing is also a critical aspect to consider. Elite-level coaches are not immune to high levels of stress and periods of burnout, which necessitates the need for early, timely interventions to prevent the onset of mental ill health, or at least the worsening of existing symptoms. For those who do experience mental ill health, supports and treatment plans need to be established, so that coaches are provided opportunities to recover within their role. It is also incumbent upon sports organizations to offer rehabilitative support after a coach departs from their role. From a sustainability perspective, offering psychological support to an individual even if they are no longer coaching, may potentially have lasting impacts in retaining these “bastions of leadership” within the high-performance environment. A mental health framework for elite-level coaches should subsequently address ways to support coaches beyond their tenure.


Occupational health nurses (OHNs) in South Korea who visit the workplace periodically could play a key role in smoking cessation. It would be helpful to assess their understanding of smoking hazards and smoking cessation methods to encourage them to provide smoking intervention services at the workplace. This study aimed to investigate the knowledge of smoking hazards and perceptions of smoking cessation methods among OHNs.We conducted an anonymous self-administered cross-sectional questionnaire survey of 108 OHN nurses employed in an occupational health service outsourcing specialized agency with 19 regional branches in Korea from July to August 2019. We assessed the perceptions of the OHNs about smoking interventions, hazards of smoking, and perceived competence to counsel smokers according to training experience, using chi-squared tests and Fisher’s exact tests.The majority of the nurses underestimated the smoking-attributable fraction for lung cancer (78.7%), chronic obstructive pulmonary disease (64.8%), and mortality (49.0%), regardless of training experience on smoking cessation, while more than half perceived their skill and knowledge to counsel patients concerning smoking as inadequate (56.5%). However, those trained in smoking cessation interventions felt more competent in smoking cessation counselling, with 52.2% and 29.3% in the trained and non-trained groups, respectively (p=0.019).The OHNs in this study underestimated smoking hazards and perceived themselves as lacking counselling skills regarding smoking cessation interventions. It is necessary to encourage OHNs to promote smoking cessation by increasing their knowledge, skills and competence in smoking cessation interventions. OHNs can act as smoking cessation advisors in workplaces. The workplace appears to be a useful setting to help people quit smoking if it has an adequate professional anti-smoking program2. Previous studies have suggested that OHNs need to be provided with opportunities to increase their smoking cessation intervention techniques and their roles as smoking advisors to promote occupational health in small- and medium-sized enterprises (SMEs) in Korea3.Occupational health nurses (OHNs) are specialized nurses in the care and well-being of people at work. They have direct contact with employees and are often approached with health-related questions and problems. The UK National Health Service (NHS) suggests that employees often see their OHNs as a ‘first port of call’ and seek advice on various health and safety-related matters, including work and non-work related conditions4. The OHNs in the OHSO SAs in Korea took over the employers’ legal obligation to protect SMEs’ employee health in accordance with the Enforcement Decree of the OSH Act5. OHNs visit SMEs monthly for occupational health management, health consultations, and healthcare education6. In 2016, 114 SAs facilitated the occupational health management activities of approximately 28000 SMEs4.In the Republic of Korea, The Enforcement Decree of the Occupational Safety and Health Act (OSH Act) allows SMEs to outsource occupational health management activities of their employees to occupational health services outsourcing specialized agencies (OHSO SAs) designated by the Ministry of Employment and Labor2 and a setting for changing the perception of smoking and reducing productivity losses and medical expenses with an entire workplace smoking cessation program7. In addition, workplace smoking cessation programs can help smokers with lower motivation levels to quit and prevent any smoking relapses8. Furthermore, a previous study of Korean workplace conditions revealed that small enterprises with <50 employees had the highest smoking rates, 56.2% among male workers, those with 50–299 employees had a rate of 53.5%, and those with ≥300 employees had a rate of 45.5% among male smokers9. They suggested that this difference was related to the lack of smoking cessation policies in smaller workplaces. The lack of resources and expertise is the main barrier towards adopting health promotion programs at smaller workplaces10. Therefore, it could be meaningful to delegate the role of promoting smoking cessation to OHNs who are in close contact with the workplaces in SMEs. However, a previous study suggested that nurses in Korea hardly participate in smoking cessation counselling and do not have the opportunity to develop the skills to counsel smoking cessation11. Despite the efficacy of nursing intervention for tobacco cessation, lack of appropriate knowledge and/or skill presents a major problem for implementation12. A study amongst Hong Kong nurses also revealed that many are not yet well prepared to intervene in tobacco cessation and that it might be due to insufficient opportunities to develop their skills for counselling smoking cessation13.The OHNs in OHSO SAs are closely associated with SMEs in Korea, and they have the potential to deliver sufficient support and advice for smoking cessation promotion in the workplace. Previous studies for workplace health promotion suggest that the workplace is a setting where large groups of smokers can potentially be reached for health promotion14, but it is a separate issue regarding how seriously and accurately smoking is considered a hazard. We aimed to investigate OHNs’ perceptions and awareness concerning smoking and assess whether their training experience in smoking cessation could influence these.It is necessary to verify the skills and knowledge of OHNs before the assignment of a role in the counselling of smoking cessation, in order to achieve successful outcomes. Thus, it is important to ascertain the perceptions and knowledge of OHNs on smoking cessation interventions. It should come as no surprise that cigarette smokers develop lung cancer and chronic obstructive pulmonary disease (COPD), the two leading causes of deathWe invited all OHNs employed in an occupational healthcare corporation with 19 regional OHSO SA branches nationwide to participate in this study. In this occupational healthcare corporation, 150 OHNs were employed to provide occupational health services to SMEs of various industries with 50–299 employees. We contacted the 150 OHNs via e-mail and conducted a questionnaire survey from July 2019 to August 2019. The e-mail contained a link to an informed consent form and a questionnaire. In total, 110 out of 150 OHSO nurses responded to the questionnaire; two subjects with inconsistent responses were excluded, and a total of 108 subjects were selected as final study subjects. The creation of the questionnaire and collection of completed questionnaires were performed using an online survey software program . The survey was conducted anonymously.15 to investigate medical students’ knowledge about smoking-related mortality, health risks, and the effectiveness of various smoking cessation methods, and also to analyze related general information and smoking status.This study utilized a previous questionnaire developed and piloted by Raupach et al.In order to conduct a survey targeting Korean OHNs, the question related to the medical school curriculum was removed, and a question about smoking status was modified and classified as current smoker, past smoker, or never smoked. The two dichotomous questions about whether respondents knew any smoker/non-smoker older than 90 years from the original study were not utilized. Several questions were added to determine the effect of various characteristics on their perception of smoking. The information obtained included sex, age, and the years of working experience as a nurse and as an OHN. We also included a question about whether OHNs had received training for smoking cessation interventions. The modified questionnaire was translated from the original English into Korean and back to English, and linguistic inconsistencies were revised.16. In particular, it was reported that there were approximately 60000 smoking-related deaths in 2012, and that the number of deaths was expected to decrease as the adult smoking rates decreased. The following three 11-point Likert scale (0–100%) questions asked OHNs to estimate the smoking-attributable fractions  for lung cancer, COPD and smoking-related disease mortality for smokers using an 11-point scale (0–100%) to assess their perception of smoking hazards. According to previous studies17, the smoking-attributable fractions for COPD and lung cancer were approximately 80–90% and 81–95%, respectively. Therefore, we regarded the ratings of <80–90% as answers that underestimated smoking-attributable health risks and following the results of the British physicians, half to two-thirds of smokers who smoke one pack a day or more will die from a smoking-related disease18; thus, the rating of 50–70% for smoking-related disease mortality was considered as the criterion to evaluate the underestimation of smoking hazards in this study. A question asked OHNs’ perceived effectiveness of several smoking cessation methods  and was determined using a 4-point Likert scale ranging from ‘very effective’, ‘effective’, ‘slightly effective’, to ‘not effective’. The OHNs were informed to consider it to be ‘very effective’ if the continuous abstinence rate was at least 30% after one year, according to the overall findings from previous studies19. The pharmacotherapy and anti-smoking drug in the smoking cessation methods was NRT originally. It was modified because the National Health Insurance Service (NHIS) in Korea covered fees for both consultation and smoking cessation aids, including not only NRT products but also varenicline and bupropion for voluntary smoking cessation clinic visits across the country since 201520. A dichotomous question asked OHNs whether they felt competent in giving advice to those seeking help to quit smoking.The questionnaire asking about smoking hazards and smoking method efficiency consisted of two open-ended questions, three 11-point Likert scale (0–100%) questions, one 4-point question and a dichotomous question. The two open-ended questions regarding smoking-related toxicity and related death toll were used: ‘In your opinion, what component of tobacco smoke is mainly responsible for the increased risk of coronary artery disease among smokers? ’ and ‘Please estimate how many people die of smoking-related diseases in Korea annually’. We referred to one of the most recent studies regarding the smoking-attributable death toll among Korean adultsThe data were analyzed using SPSS version 21.0 . The level of significance was set at p<0.05. The frequency analysis of training experience for smoking cessation interventions was conducted according to the demographic characteristics of the participants. The differences in training experience for smoking cessation interventions according to sex, age, knowledge, and smoking behavior of family members were investigated using chi-squared tests. Statistically significant differences in training experience with respect to years of working experience as a nurse and as an OHSO OHNs were evaluated using an independent t-test. Frequency distributions were used to describe the responses of OHSO nurses to the open-ended question about the components of tobacco smoke related to increased coronary artery diseases among smokers and the question asking about their perception of the effectiveness of several smoking cessation methods. Chi-squared tests were used to determine the differences in smoking cessation education and categorical variables, such as number of smoking-attributable deaths and smoking-attributable fractions of mortality, lung cancer, and COPD. If the expected frequencies were too low (>20% of the cells had an expected count of <5), Fisher’s exact tests were used instead of the chi-squared tests. The open-ended question estimating smoking-attributable deaths in South Korea were equally categorized into five levels between 0 and 100000, and the differences in smoking cessation education and categorical variables were analyzed using the chi-squared test.The demographic characteristics of participants, according to having and not having training experience for smoking cessation interventions, are presented in Among the 108 respondents, 99 nurses gave 149 collectible answers with multiple responses to the open-ended question regarding the components in tobacco smoke responsible for the increased risk of coronary artery disease among smokers . AlthougThe answers to ‘Please estimate how many people die of smoking-related diseases in Korea annually’ are presented in The OHNs were asked to share their thoughts regarding the effectiveness of smoking cessation methods . The majParticipants were asked: ‘Do you think you have the expertise to help smokers who want to quit smoking?’ . More th17, and that half to two-thirds of smokers who smoke ≥1 pack a day will die from a smoking-related disease19.This study investigated the perception of OHNs regarding smoking hazards as well as the effectiveness of smoking cessation methods by asking them to estimate the risk of smoking and the effectiveness of these methods. We also analyzed the associated factors influencing the awareness of OHNs regarding the smoking hazards and perceived competence towards smoking cessation. More than half of the OHNs in this study thought that smoking was responsible for <70% of lung cancer and COPD cases or smoking was responsible for <50% of smoking-related disease mortality. This is a much-underestimated answer, compared to the smoking-attributable fractions for COPD and lung cancer being reported as approximately 80–90% and 81–95%, respectively, from previous studies21, the majority of OHNs regarded ‘will power alone’ as very effective and more effective than the scientifically proven and recommended methods, such as physicians’ advice and pharmacotherapy with behavioral support23. Acupuncture, which appears to have no scientific evidence in previous work24, was overestimated as effective as pharmacotherapy, and even previous training experience on smoking cessation did not improve acknowledgement of the importance of smoking cessation methods. This underestimation of physicians’ role in smoking cessation interventions and proven smoking cessation methods can adversely affect smoking cessation attempts and policies. The OHNs with these misconceptions would be passive in referring smokers to smoking cessation intervention clinics and fail to provide smokers with proper smoking cessation information and aids.Their knowledge of the effectiveness of smoking cessation methods was also insufficient compared to reported literature; given that an unassisted quit rate was reported at only 2–3% in the literature18. Obtaining nicotine from NRT has the potential to assist smoking cessation attempts with fewer adverse events and can reduce daily cigarette consumption25. If OHNs regard smoking and nicotine synonymously within the context of abusing agents and cardiovascular risk factors, they would not recommend NRT to smokers and the OHNs who value unassisted willingness would be passive in referring smokers to smoking cessation intervention clinics. They might fail to provide smokers proper smoking cessation information and aids.In addition, the OHNs in our study also had misunderstandings about the harmful substances of cigarettes. Many OHNs believed that nicotine is mainly responsible for coronary artery diseases. These misunderstanding and lack of knowledge is noteworthy given the counselling role of Korean OHNs in SMEs, although this misunderstanding has been consistent also in previous studiesThe estimated number of smoking-attributable deaths per year and knowledge of the overall health risk of smoking were poor in our study. If these two fatal diseases (lung cancer and COPD) were caused by smoking, deaths could be attributed to smoking. It could be stated that the OHNs in our study did not regard smoking as a serious health risk and tended to underestimate the actual severity of smoking. Moreover, their training experience for smoking intervention did not affect these results.26. Our results showed that nurses with training on smoking cessation interventions felt more competent in smoking cessation counselling, although the training experience did not make a significant difference in the OHNs’ perception of smoking hazards. Notably, educational programs for nurses in supporting smoking cessation efforts could encourage more nurses to engage in smoking cessation interventions27; however, if healthcare professionals had incorrect background knowledge and perceptions regarding smoking cessation or smoking hazards, ineffective methods would be recommended.More than half of the OHNs believed that they did not have adequate skills and knowledge to counsel patients about smoking. Furthermore, many OHNs never had specific education on smoking cessation and had never been encouraged to undergo such training. The issues regarding the lack of counselling knowledge concerning smoking and the necessity of creating training opportunities regarding smoking cessation have been raised in previous studies28 and the workplace is a favorable setting for smoking cessation because smokers’ social environment, particularly colleagues, are strongly associated with success in quitting29. The workplace smoking cessation programs show encouraging results, but the lack of resources and expertise is the main barrier towards adopting health promotion programs at smaller workplaces10. OHSO SA health management can be properly utilized for smoking cessation programs at SMEs. However, they can only passively conduct smoking cessation interventions unless they are prepared and equipped to provide qualified services. However, if OHNs who are well-prepared to deliver qualified help could advise workplace smokers during their periodic health consultation, it would be sufficient for the smoking cessation program at the workplace. Our research can serve as a basis for creating awareness about such high-quality smoking cessation services among nurses in the workplace or the general community.Previous studies have suggested that the workplace setting offers an opportunity to recruit large numbers of smokers while having a comparable effect with other settings such as clinicTo the best of our knowledge, this study is the first to report how OHNs, who visit the workplace regularly, underestimate smoking hazards and proven smoking cessation aids. Our findings also indicate that the experience of nurses in smoking cessation education made a difference only in their competence in smoking cessation counselling. We asked the OHNs to estimate objective values related to smoking hazards from recent research, and the estimated answers were derived from their knowledge concerning smoking hazards.As this study was the first attempt to investigate the background perception of nurses regarding smoking cessation promotion, it has some limitations. First of all, our study was conducted based on very limited conditions to be able to be generalized. We utilized the questionnaire from a previous study which did not inform on the reliability and validity assessment of the questionnaire. It was uncertain if the participants were evaluated on their perception and knowledge of smoking-related issues by their answers. The participants were also limited, all being OHNs employed in a single OHSO SA in Korea. There is a potential bias and uncertainty of generalization of the results to other nurses and OHNs in Korea. Subsequently, to generalize the research results, it is necessary to conduct further questionnaire evaluations of subject groups. Third, despite using data from widely cited research in the field of smoking and related diseases, some referenced studies are relatively old, and there may be differences in specific values related to the smoking-attributable fraction of diseases, mortality, and the effect of anti-smoking aids and treatments. Finally, the nurses’ experience in smoking intervention was assessed only by self-reports, potentially rendering our results less reliable. However, we found that the experience of smoking cessation promotion education could make a difference in self-competence about smoking cessation promotion.This study aimed to investigate OHNs’ perception and knowledge concerning smoking and assessed whether their training experience in smoking cessation could influence their perception and awareness. The OHNs underestimated smoking hazards, and the effectiveness of various smoking cessation methods; their smoking cessation intervention training experience made them feel more confident in smoking cessation counselling but their perception regarding smoking was not significantly different. There is a need for proper education on smoking cessation for the OHNs within smoking cessation programs at SMEs in Korea. When OHNs have the right knowledge about the smoking hazards and smoking cessation methods, and have confidence based on appropriate skills in smoking cessation promotion, OHNs would be able to effectively contribute to workplace smoking cessation interventions.Click here for additional data file.


Recent studies explored the general performance of varying machine-learning techniques, however, the workflow engineering part was of secondary importance. For the sake of applicability, such a tool should be generic, data driven, and offer the possibility to be easily adapted to individual workflows for experimental design and data processing.Including ion mobility separation (IMS) into mass spectrometry proteomics experiments is useful to improve coverage and throughput. Many IMS devices enable linking experimentally derived mobility of an ion to its collisional cross-section (CCS), a highly reproducible physicochemical property dependent on the ion’s mass, charge and conformation in the gas phase. Thus, known peptide ion mobilities can be used to tailor acquisition methods or to refine database search results. The large space of potential peptide sequences, driven also by posttranslational modifications of amino acids, motivates an ionmob, a Python-based framework for data preparation, training, and prediction of collisional cross-section values of peptides. It is easily customizable and includes a set of pretrained, ready-to-use models and preprocessing routines for training and inference. Using a set of ≈21 000 unique phosphorylated peptides and ≈17 000 MHC ligand sequences and charge state pairs, we expand upon the space of peptides that can be integrated into CCS prediction. Lastly, we investigate the applicability of in silico predicted CCS to increase confidence in identified peptides by applying methods of re-scoring and demonstrate that predicted CCS values complement existing predictors for that task.We created https://github.com/theGreatHerrLebert/ionmob.The Python package is available at github:  Ion mobility separation (IMS) adds an additional dimension of separation. Its functionality is based on the fact that in the presence of an electric field, small, compact ions will behave differently when flying through a cloud of charge-neutral gas than larger ones  improves throughput and coverage of proteomics experiments , but not for devices involving high fields such as field asymmetric ion mobility spectrometry  value of the ions by applying kinetic theory that links experimentally determined reduced ion-mobilities to their momentum transfer collision integral through the Mason–Schamp equation  instances were aggregated and their occurrences tracked. In order to distinguish between differently folded populations of peptides with the same charge state and sequence but notably different CCS values, modality classes were assigned. Features with identical charge and sequence that diverge the boundary of 2-times the standard deviation to the main feature are considered to be secondary features. Thereby, a distinction between unimodal and bimodal distributions of CCS values for a feature is established. Within the bimodal fraction of features, a main feature is determined based on the peptide mode with highest occurrence. Features that displayed CCS values within the boundary of 2-times the standard deviation to the main feature are considered as part of the main feature and therefore aggregated/fused. The difference in CCS values for the latter features are attributed to measurement inaccuracies. The resulting CCS value is the occurrence-weighted average of all -duplicates within the same modality class. In case of multi-modality of a feature, only the main feature was kept.We downloaded the peptide identification tables from the following publicly available datasets acquired in timsTOF instruments.https://github.com/theislab/DeepCollisionalCrossSection, accessed 10.07.22). The combined dataset contained 718 917 unique pairs of charge state and sequence.The tryptic peptide training and test sets published by The tryptic peptide results published by The results published by We extracted 42 sequence, charge state pairs acquired using et al. and each of the other datasets . Using this dataset as reference is practical, as it holds by far the most sequences. This aligns the means of all observed CCS values in different datasets and is necessary to avoid systematic error.A dataset specific, linear shift in CCS was calculated by matching sequence and charge state pairs identified in both the dataset obtained from Meier A concatenation of training and test sets published by Initial square-root fit was performed separately for each charge state using SciPy, see We downloaded the CCS predictor tools described by pepdata Python package  was used to calculate scalar features for peptide sequences. The package provides scalar descriptors of different amino-acid properties like hydropathy or polarity as mappings from a given amino acid to the respective value. For the scalar descriptors volume, polarity, hydropathy, hydrophilicity, solvent-exposed area, accessible surface area, accessible surface area folded, local flexibility, and pK side-chain, we calculated their normalized value by summing over the individual contributions of amino acids per sequence and divided by the sequence length.The We tested the impact of using CCS predictions by adding CCS features as feature set to the current implementation of MS²Rescore , we compared it with three previously published deep predictors: Other studies predicting CCS made use of the Pearson correlation coefficient as an additional metric. However, we observed that the square-root baseline already had a correlation value of In most proteomics workflows, the MS is configured to skip the fragmentation of singly charged ions or they are simply not considered for peptide identification during data processing . This chAs mentioned above, CCS values are never directly measured but derived from experimentally determined ion-mobilities by e.g. the Mason–Schamp equation or using a calibration curve . HoweverThe learned residues of peptide CCS values with respect to the initial fit use an embedding  to represent amino acids as dense vectors before being fed to the GRU units. This gives the opportunity to inspect how unmodified and modified amino acids are grouped relatively to each other in the embedding vector space by the network. To explore it, we evaluated the agglomerative clustering of amino acid features as shown in Besides evaluating the individual relationships between amino acids in the embedding space, we also explored the linear relationships between sequence-wise predicted deep residues and additive scalar properties that can be directly calculated from amino acid sequences. A recent study, in-silico predicted CCS for phosphorylated peptides into identification workflows might therefore be an excellent opportunity to be specifically integrated, which is already under commercial development .In a recent study, In summary, the GRU model implemented in ionmob not only enables the prediction of peptide CCS values from tryptic, nontryptic and modified peptides but also allows the evaluation of feature-specific contributions at the amino acid, sequence, and PTM levels.To establish prediction tools, one highly relevant question is whether or not the ion-mobility signal distribution should be taken into account when predicting CCS values. So far, all approaches including our own were implemented as maximum likelihood estimators. The simplification allows for a more straightforward formulation of the mobility modeling task. However, following this approach might be disadvantageous if the underlying assumption that signal distribution displays a single maximum does not hold. Notably, we and others observed that single peptide sequences can sometimes have multiple conformations in the gas-phase .a priori if it might be necessary to predict more than one CCS value. Due to the relatively low number of candidates and potential stochastic processes driving multi-modality, we consider this to be an open challenge for future investigations (Similar to the approach described by igations .2Rescore (Using CCS predictions as an additional feature set in rescoring of database search results can provide increased performance to further separate true from false targets and gain confidence in the identified PSMs. To evaluate the value of CCS prediction for identification rescoring, we incorporated the ionmob models to the features used by MS2Rescore . When in2Rescore . Moreove2Rescore . It demo2Rescore . CCS feain silico predicted CCS values can be used to increase confidence in peptide identifications by applying methods of rescoring. In summary, ionmob is an easily deployable package for the training and incorporation of peptide CCS prediction.We implemented ionmob, a framework for preprocessing, training and inferring peptide CCS values. ionmob includes a novel network architecture that combines a simple function fit with gated recurrent units, helping to stabilize and speed up training and make model outputs easier to interpret. By including phosphorylated peptides and MHC ligands also covering singly charged ions into the training set, we extend the applicability of our model, enabling the accurate prediction of a wider variety of PTMs than recently published models. Furthermore, our results suggest that local flexibility of peptides is an additional driving factor of increased CCS and confirm recently published findings that phosphorylation lowers CCS, which could be indicative of charge interaction-based compaction in the gas phase. Lastly, we demonstrate that btad486_Supplementary_DataClick here for additional data file.


Iron plays an important role in the development of perihematomal edema (PHE) in the setting of intracerebral hemorrhage (ICH). Cerebral iron is increased via direct hemoglobin release in ICH, and several studies have investigated the use of iron-chelating agents to mitigate its toxicity. However, the effect of systemic iron administration, corroborating the reverse concept, has never been investigated or reported clinically. We report the first case of systemic iron administration in the setting of hemorrhagic traumatic brain injury (TBI).A 46-year-old woman was admitted to the hospital with acute moderate-to-severe TBI. Her head computed tomography (CT) scan showed bifrontal hemorrhagic contusions with mild PHE. She was started on hypertonic saline 3% continuous infusion and her condition remained stable initially. She was found to be anemic and was given intravenous iron sucrose. Shortly after iron administration, her mental status declined, and left pupil became dilated and sluggish. Repeat CT demonstrated significantly worsening PHE. This prompted maximum hyperosmolar therapy and external ventricular drain (EVD) placement which both were weaned off slowly due to liable ICPs. She was discharged home after a 25-day hospital stay.We believe this is the first report of exacerbating PHE accompanied by clinical decline after intravenous iron administration in the setting of acute hemorrhagic brain contusions. Though the effects of systemic iron administration on brain edema and the treatments targeting cerebral iron are poorly understood, the administration of systemic iron in acute TBI seems to be detrimental. More research is needed to address iron toxicity in TBI. Our case adds to the growing evidence for such a pathway in the treatment of ICH and TBI. Iron has an important role in the development of perihematomal edema (PHE) associated with intracerebral hemorrhage (ICH). Though the topic is not well understood, free iron is considered highly toxic to neural tissue due to its ability to form free radicals and cause significant oxidative stress. In the setting of ICH, free iron is released from the hematoma via lysis of red blood cells . The acuHerein, we report a case of acute traumatic brain injury (TBI), with bifrontal hemorrhagic contusions, in which the patient experienced a decline in neurological status with exponentially increased perihematomal brain edema concurrent with the administration of intravenous (IV) iron. This case potentially demonstrates the toxic effect that elemental iron has on the brain and calls to caution and avoidance of iron administration in the setting of acute brain injury. To our knowledge, this is the first reported case to show such effect as a consequence of systemic IV iron administration in humans. It also highlights its potential as a therapeutic target with more effective treatments than what have been studied –5.A 46-year-old woman with no comorbidities was admitted to the intensive care unit (ICU) with acute TBI after she was struck, while jogging, by a motor vehicle traveling at 5 mph. Computed Tomography (CT) imaging revealed bifrontal small subdural hematomas with underlying hemorrhagic contusions, along with small subarachnoid hemorrhage Fig. a. She waBetween days 6 and 10 of hospital stay, initial attempts to wean hyperosmolar therapy demonstrated rebounding increase in ICP with correlating change in mental status warranting a slower wean. She was extubated on day 11 as her exam improved steadily, the EVD was removed on day 15, and her GCS remained stable at 14–15. The patient was discharged to a rehabilitation center after a 25-day hospital stay. She followed up with physical therapy and rehabilitation medicine where she continued to make progress in her recovery.Iron accumulates within brain parenchyma after ICH. Its ability to increase oxidative stress within cells has led to the belief that it plays a crucial role in secondary brain injury and therefore affects clinical outcome. Consequently, iron has been an appealing therapeutic target in the management of ICH. Deferoxamine, an iron-chelating agent, was shown to attenuate brain edema and neurological deficits in animal models . HoweverNevertheless, despite the iron chelator showing no difference in patient outcome in clinical trials, our patient’s malignant PHE progression could be a clinical demonstration of systemic iron's ability to cause brain injury. Administration of IV iron co-occurred with significant worsening of the patient’s mental status, and exponentially worsening PHE confirmed with serial CT imaging. Fig.  NormallyThe limitation of the findings in this case report is that it is a single instance in which iron administration was followed by worsening PHE. As such we lack sufficient statistical power to indicate causation over correlation. However, given the extensive evidence of iron toxicity to the brain, correlation of iron and brain edema, and lack of significant confounders, it is reasonable to indicate that the iron could have caused our patient’s worsening course.The serial CT imaging showing the malignant course of the edema after iron was administered to our patient further potentiates our implied theory.Healthcare providers should be aware of the potentially harmful effects of administering iron to a patient with sustained BBB disruption. During disruption, systemic iron can cross the barrier at liberty, enabling iron overload and increasing oxidative burden within the brain. Iron has been consistently shown to be toxic to the brain in preclinical studies, though clinical evidence is lacking for effective intervention. This case potentially demonstrates the ability of systemically administered iron to damage the brain in certain clinical settings. Eliminating iron from the brain or rendering it unable to form free radicals may still be a plausible therapeutic target in the management of ICH; pharmacological, surgical or both. We suggest further clinical research, potentially altering the administration regime or transport medium, selecting a drug with a different mechanism of action, or possibly combining iron-chelators with hematoma evacuation to rule out iron elimination’s potential as a therapeutic target in the management of ICH.


Intimate partner violence (IPV) is highly prevalent in low-income and middle-income countries and has been a major obstacle towards reaching global health targets for women and children. We aimed to investigate cross-sectional and longitudinal associations between IPV victimisation and maternal parenting practices of young children in a population-based birth cohort study in Brazil.The 2015 Pelotas Birth Cohort is an ongoing, prospective cohort, including all hospital births occurring between Jan 1 and Dec 31, 2015, in the city of Pelotas, Brazil. When children were aged 4 years, mothers reported on emotional, physical, and sexual IPV victimisation in the past 12 months. Parenting outcomes were assessed through filming the mother and child in interactive tasks at age 4 years and maternal interviews at ages 4 years and 6–7 years. Interactive tasks were filmed at the Centre for Epidemiological Research facilities. Directly observed outcomes included negative  and positive  parenting interactions independently coded by a team of psychologists. Self-reported parenting was measured using the subscales on quality of parent–child relationship, positive encouragement, parental consistency, and coercive behaviour of the Parenting and Family Adjustment Scales questionnaire. Unadjusted and adjusted linear regression analyses were performed to assess the associations.Of the 4275 livebirths enrolled in the cohort, 3730 mother–child dyads were included in our analytical sample at age 4 years and 3292 at age 6–7 years. After adjusting for all potential confounders, emotional IPV and physical or sexual IPV were associated with the following self-reported parenting outcomes: poor parent–child relationship quality , lower parental consistency , and more coercive behaviour  at age 4 years. Associations were not observed for self-reported positive encouragement and filmed parenting outcomes in fully adjusted models. Longitudinally, IPV at age 4 years predicted similar outcomes when children were aged 6–7 years.In this large cohort study, maternal IPV victimisation was consistently associated with poorer parent–child relationship, decreased parental consistency, and increased harsh parenting reported by mothers of young children. As well as initiatives to prevent IPV, parenting interventions focused on supporting the capacity of caregivers to provide nurturing care delivered at key stages early in the life course are crucial.Wellcome Trust.For the Portuguese translation of the abstract see Supplementary Materials section. Violence against women by male partners is a global public health concern affecting the lives of millions of women and their children.Although there is a considerable evidence base on the harmful effects of parental conflict on parent–child interactions, which is implicated in important theories such as the spillover hypothesis—suggesting an interdependency between the feelings experienced across different family relationshipsEvidence before this studyWe found two systematic reviews on maternal intimate partner violence (IPV) victimisation and parenting practices. The first review was carried out by Chiesa and colleagues in 2018 and included 33 quantitative studies with modest effect sizes for the association between IPV victimisation and harmful parenting practices , but high levels of heterogeneity across studies. The second review was conducted by Sousa and colleagues in 2021 and integrated findings from 64 studies including quantitative, qualitative, and mixed methods, to understand more deeply how mothers experience and respond to the effects of IPV on their parenting. The analysis suggested that IPV can undermine parenting, often through its effects on mothers’ sense of efficacy and mental health. Both reviews highlighted several pervasive methodological problems of the studies, which used narrowly focused samples without clear temporal ordering of variables; moreover, most studies had been conducted in high-income countries (mainly the USA).Added value of this studyThis is the first prospective population-based birth cohort study to investigate the associations between maternal IPV victimisation and parenting outcomes across early to mid childhood in low-income and middle-income countries (LMICs). In addition to examining associations with harsh parenting and physical punishment, which have been the focus of the few studies carried out in LMICs, we evaluated the effects of IPV on a range of positive aspects of maternal parenting relevant to child development. This study adds to the scarce data employing observed measures of parenting that provide both a more independent assessment and an investigation of more subtle aspects of parent–child interactions, in contrast to general behaviours, which are commonly reported in interviews and self-report questionnaires. We were also able to examine the potential distinct effects of emotional IPV and physical or sexual IPV on parenting, which is not commonly seen in the field. We found that IPV victimisation experienced by the mother  was consistently negatively associated with parent–child relationship quality and parental consistency, and was positively associated with coercive behaviour when children were aged 4 years and 6–7 years.Implications of all the available evidenceOur findings contribute strong evidence to the literature on the adverse effects of violence against women, and underscore the important role that IPV prevention strategies can play in enhancing the quality of mother–child interactions. As well as initiatives to prevent IPV, parenting interventions focused on supporting the capacity of caregivers to provide nurturing care  delivered at key stages early in the life course are crucial for improving maternal and child wellbeing.Scarce evidence is available on the links between IPV and broad maternal parenting practices in LMICs. Previous cross-sectional studies have focused on the specific association between IPV and violent discipline of children, with most showing positive associations.Theoretical mechanisms linking IPV with compromised parenting include mental health difficulties arising from IPV, diminished maternal confidence and sense of identity in their role as caregivers, and violent partners controlling women's capacities and resources to care for their children.The 2015 Pelotas (Brazil) Birth Cohort Study is a population-based, prospective cohort study, including all children born in 2015 in Pelotas, a city in southern Brazil with a population of approximately 340 000 people. Of the 4333 livebirths that took place in the city maternity hospitals from Jan 1 to Dec 31, 2015 , 4275 (99%) children were enrolled in the cohort and have been followed up since then. At the last follow-up, when children were aged 6–7 years, the response rate was 92%. Detailed methods of the cohort study and each follow-up have been published elsewhere.Information on recent IPV victimisation for mothers was collected through confidential interviews conducted by trained female interviewers using the WHO questionnaire at the 4 years follow-up. The instrument was previously validated in Brazil,Potential confounders included maternal and family characteristics, which were assessed from the time of delivery  until children were aged 4 years. A representation of the assumptions about the relationship between variables is presented in Maternal parenting practices examined in the current study are described in detail in Descriptive statistics are provided in terms of absolute and relative frequencies for categorical variables, and means and SD, medians and IQR, and ranges  for continuous variables. Outcomes were standardised  to allow comparability between measures of associations for all parenting variables. Multiple linear regression analyses were performed to assess the association between IPV and maternal parenting outcomes. Three models were included for each outcome: unadjusted results (model 1), results adjusted for all confounders except previous depressive symptoms (model 2), and fully adjusted results controlling for all the potential confounders (model 3). The option to have two separate adjusted models (with and without previous depressive symptoms) was due to the potential for depression to be a consequence of persistent IPV exposure, which was not assessed in the present study as we did not have previous measures of IPV (before the 4 years assessment).16The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report..Of the 4275 participants who were enrolled in the perinatal study between Jan 1 and Dec 31, 2015 , 3730 mother–child dyads comprised the analytical sample at age 4 years and 3292 at age 6–7 years . Mean agCorrelations between main exposures, potential confounders, and maternal parenting outcomes are present in Associations between maternal IPV victimisation and harsh parenting outcomes showed that emotional and physical or sexual IPV were associated with increased self-reported coercive parenting but not with directly observed coercive parenting. Adjustment for confounders did not affect the associations significantly. Results from model 2 showed that IPV victimisation was associated with an average increase of 0·25 SD in coercive behaviours for both IPV indicators  at age 4 years. At age 6–7 years, effect sizes were a little higher . When additionally accounting for depression, estimates were slightly attenuated but remained significant (p<0·001) at both timepoints.After applying the Benjamini-Hochberg correction, all significant associations remained unchanged .Results from the sensitivity analysis suggested that a dose–response relationship exists between the number of emotional IPV abusive acts and worse parent–child relationship quality at age 4 years and lower parental consistency at both ages 4 years and 6–7 years .We investigated cross-sectional and longitudinal associations between maternal IPV victimisation and a broad range of parenting practices among mothers of young children in a Brazilian population-based cohort. We newly evaluated both self-reported maternal parenting practices, referring to general behaviours over an extended time frame (the previous month), and more nuanced aspects of mother–child interactions measured through direct observations. We were able to separate the potential distinct effects of emotional abuse and physical or sexual abuse. This distinction is important because, despite being the most common subtype of IPV, research on the consequences of emotional IPV has often been neglected or not carefully investigated, particularly independently of physical or sexual IPV.There were interesting differences in the findings from the direct observations compared with the maternal reports; this was particularly the case for coercive behaviour, for which associations greatly differed depending on the method of assessment. One potential explanation is that direct observations of mother–child interactions reflect only a snapshot, albeit more refined, of real-life family interactions, whereas self-reported parenting practices reflect more general maternal behaviour. There is evidence that maternal behaviours are affected by expectations in laboratory sessions in the presence of the researcher, and therefore mothers might exhibit less coercive behaviour. Another hypothesis is that harsh parenting manifests sporadically , and this might be remembered by mothers, but not captured by the punctual observations. However, maternal reports could also be affected by mothers’ mental health status, leading them to report more difficulties in parenting. Although not necessarily measuring equivalent parenting behaviours, the use of validated and complementary measures can be considered a strength of the present study as no previous study has tested these associations with both types of measures.There is growing international evidence on the intersections of IPV against women and violent discipline of children by caregivers within households.Our results showing negative associations between IPV victimisation and positive parenting outcomes extend the existing literature in LMICs that has primarily focused on negative parental practices such as harsh parenting.There are some limitations to be considered in this study. Under-reporting of experiences of violence is well described in the literature. Furthermore, IPV experiences beyond the previous year were not assessed in this cohort and this could contribute to dilute estimates as we are potentially including women who experienced IPV before the time frame assessed in our reference category. In this sense, further adjustment for maternal depressive symptoms is likely to also underestimate the magnitude of our estimates given the possibility that symptoms were a consequence of chronic IPV exposure. Another aspect to consider is that earlier IPV experiences  might have resulted in relationship termination (and thus no more recent IPV), but could still have negatively influenced parenting outcomes and caused equal harm. We should be aware that, although not the focus of the current analysis, many pathways of resilience have been described in the literature.The current study reveals that effects of IPV are specific to the domains of parenting captured in self-reports, rather than every aspect of parenting, even when considered at a more nuanced level. The findings add to the literature, pointing to the adverse consequences of IPV victimisation on mother–child dyadic relationships and underscoring the important role of interventions focused on improving caregiver's abilities to provide nurturing environments and parental practices  that are more supportive for children exposed to violence within households. In this context, strategies addressing contextual obstacles to more positive parenting  also seem warranted. Finally, IPV primary prevention interventions are crucial for improving maternal and child wellbeing.http://www.epidemio-ufpel.org.br/site/content/faculty/ for a list of key faculty members) and completing the application form (http://www.epidemio-ufpel.org.br/site/content/studies/formularios.php). Researchers with successful applications will receive a dataset including the requested variables and unique participant identification.Applications to use the data can be made by contacting the researchers of the 2015 cohort (see Lancet Commission on gender-based violence and maltreatment of young people. All other authors declare no competing interests.CVNC and JM report consulting fees as part of the


The circadian rhythm of blood pressure (BP) is associated with a high span during the awake period and a low span during the sleep period. Of interest is that cardiovascular (CV) events occur more frequently in the early morning period, the time when BP and heart rate rise steeply.To provide an overview of circadian BP and its correlation with adverse clinical outcomes and to discuss strategies for optimizing BP control over 24 hours.Patients who have an excessive morning surge in BP and those who lack the normal nocturnal BP fall (nondippers) have been shown to have an excessive incidence of strokes, heart failure, and other CV events. While there are numerous pathophysiologic mechanisms underlying abnormalities in the 24-hour BP profile, including abnormalities in sympathetic nervous system activity, salt and volume balance, and activation of the renin-angiotensin aldosterone system, for many patients the mechanisms remain unclear. Nevertheless, several of these known abnormalities can be modified by clinical interventions, including proper timing of antihypertensive drug therapy and use of classes of antihypertensives for which a substrate exists to induce a pharmacologic effect. It is particularly important to use therapies that will provide control throughout a 24-hour dosing interval.While interventional strategies have not yet been shown to alter clinical outcomes, it is important to be cognizant of their physiologic basis and take them into consideration when making decisions regarding appropriate antihypertensive therapy.


Addressing complex health and social needs requires cross-sector collaboration to deliver medical, social, and population health services at the community level. Capacity in community health and social services networks may be constrained in regions like Appalachia due to the combined effects of rurality and persistently poor health and social outcomes. One way that cross-sector networks serving low-resource communities can expand their capacity is by engaging partners, like health insurers, who can leverage resources from outside the local area.This study examines insurer connectivity in cross-sector networks across Kentucky’s geographic regions and the association between connectivity and the probability of an individual experiencing a preventable hospitalization.A cross-sectional design was used that linked data from the National Longitudinal Survey of Public Health Systems (NALSYS) with 2018 patient-level Kentucky hospital discharge data to examine the association between insurer connectivity in community networks and preventable hospitalizations across urban, rural non-Appalachian, and Appalachian regions.p < 0.01).Analysis of the data shows substantial geographic variation in the association between insurer connectivity in community networks and preventable hospitalization. Insurer connectivity in rural Appalachian communities was associated with lower likelihood that an individual was admitted for a preventable hospitalization ( Findings suggest insurer connectivity in cross-sector community health and social services networks has the potential to strengthen network capacity to address preventable hospitalizations and improve health outcomes and well-being for the people of Appalachia. Social determinants of health—such as food insecurity, housing instability, and household financial strain—contribute to high levels of disease burden and premature mortality in the U.S., but medical providers often lack the resources and expertise needed to address these issues effectively.4Rural communities are likely to face limited capacity in community health and social services networks due to numerous unique characteristics. Rural areas have fewer healthcare providers, less access to quality clinical care, and limited social resources, such as housing, food and transportation assistance programs.8One way that cross-sector networks serving resource-constrained communities can expand their capacity is by engaging partners who can leverage resources from outside the local area. Health insurers, for example, typically serve large geographic service areas within and across states and have access to expertise, information, and financial assets that often exceed the resources available to more localized community-based organizations. Insurers may contribute to the community networks operating within their service areas to improve the health and social resources available to their members, possibly making larger contributions to networks and communities with greater unmet needs. This overlooked form of cross-subsidization may play a role in strengthening networks in areas with less community health and social services network capacity.Evidence on the association between insurer participation in community health and social services networks and improved health outcomes is limited. To help fill this gap, this study used hospital discharge data linked with health and social services network data to examine the association between insurer connectivity in cross-sector networks and preventable hospitalizations across geographic regions in Kentucky. Kentucky was selected for this analysis based on both the availability of comprehensive community network data and the geographic diversity of the state. It has three distinct urban, rural non-Appalachian, and rural Appalachian regions. Preventable hospitalizations was selected as the primary outcome based on prior research linking hospitalizations to both patient and community-level socioeconomic conditions.Data from the National Longitudinal Survey of Public Health Systems (NALSYS) were linked with 2018 patient-level Kentucky hospital discharge data to examine the association between insurer connectivity in community health / social services networks and preventable hospitalizations across urban, rural non-Appalachian, and Appalachian regions. NALSYS is the only national and longitudinal data source that captures data on cross-sector collaboration in the delivery of population health activities.NALSYS data were first collected in 1998 with subsequent waves in 2006, 2012, 2014, 2016, 2018, and 2020.8Using the Agency for Healthcare Research and Quality’s (AHRQ) Prevention Quality Indicators definitions, patient-level preventable hospitalization was identified via discharge data in four categories for each Kentucky county.betweenness centrality. Betweenness centrality is a common measure used in social network analysis methods that measures the extent to which one actor connects others in the network.Data on insurer connectivity in the population health network were calculated using NALSYS to generate insurer Descriptive statistics were generated to examine preventable hospitalization rates and insurer connectivity in community networks across the three geographic regions. Multivariate logistic regression models were then used to identify the association between insurer connectivity and the probability of an individual being admitted for a preventable hospitalization. The primary explanatory variable was operationalized as categorical with networks having ‘no’, ‘low’, or ‘high’ insurer connectivity. Models were run first for the pooled sample including all community networks. Separate models were then run for each geographic region to determine if there were variations in associations between the three regions. Last, a set of models for the rural Appalachian region alone were run to determine if differences in the association between insurer connectivity and the probability of preventable hospitalization exist based on the patient’s coverage type. Patients were categorized into three subgroups: Medicare, Medicaid, and privately insured. Patients who were uninsured were excluded from the analysis due to small sample size.All models controlled for a set of community socioeconomic, demographic, and healthcare system supply characteristics pulled from the Area Health Resource File (see figure notes for the full list of variables). Patient race, age, and payer were also controlled for in all models, apart from the last analysis. Standard errors were clustered at the community network level to account for patient nesting within communities.Preventable hospitalizations accounted for 10%–13% of hospitalizations in KY communities in 2018, with rural Appalachian communities having the highest rate . Most prp < 0.01). No significant associations were found between insurer connectivity and preventable hospitalizations in urban community networks. Interestingly, low insurer connectivity in rural non-Appalachian community networks was associated with increased probability of an individual experiencing a preventable chronic hospitalization (p < 0.05). Otherwise, there were no statistically significant associations in rural non-Appalachian community networks.Results from multivariate logistic regression found statistically significant associations between high insurer connectivity and all four preventable hospitalization categories in rural Appalachian communities . High inp < 0.01). High insurer connectivity was associated with reductions in the probability of preventable hospitalization in the acute and chronic hospitalization composites in the Medicare and Medicaid populations.Analysis of subgroups by payer within rural Appalachian regions found substantial variation in the association between the probability of preventable hospitalization in community networks where insurer connectivity is higher based on coverage type (p < 0.05). Similarly, high insurer connectivity was associated with an almost one-percentage-point increase in the probability of Medicare patients experiencing a diabetes-related preventable hospitalization (p < 0.05). Among the privately insured, high insurer connectivity was associated with reductions in the probability of all preventable hospitalization composites, apart from chronic hospitalizations. Interestingly, low insurer connectivity was associated with higher probability of experiencing a preventable hospitalization across all composites for privately insured patients in Appalachian community networks.Low insurer connectivity compared to none was associated with a two-percentage- point increase in acute preventable hospitalization probability in Appalachian Medicare patients (Results suggest substantial geographic variation in insurer connectivity in community health / social services networks and its association with the probability of an individual being admitted for a preventable hospitalization. High insurer connectivity in rural Appalachian communities was associated with lower likelihood that an individual was admitted for a preventable hospitalization compared to those communities with no insurer connectivity. There was not a similar association in urban and rural non-Appalachian communities across the state. In fact, low insurer connectivity was associated with a higher probability of chronic preventable hospitalization in rural non-Appalachian communities.While initially surprising, these findings may arise from several factors: rural Appalachian communities have worse health and social outcomes and may have fewer resources available to bolster capacity in community networks. High insurer connectivity in community networks may help strengthen the connections between sectors by bridging organizations that may not have previously worked together. Such action is likely to bring new resources and perspective to collaborative efforts and facilitate the meeting of both health and social needs in a complex population. Historically, more populated communities have had stronger health and social services networks that offer a greater range of services while engaging a broad set of multisector partners.Results from the subgroup analysis of preventable hospitalizations by payer type in rural Appalachian communities suggest that the strongest associations with insurer connectivity were concentrated in the Medicare and Medicaid patient populations. Medicare patients are at higher risk of preventable hospitalization resulting from poorly managed health conditions.Interestingly, while there was a similar pattern in high insurer connectivity and lower preventable hospitalization probability in privately insured patients in Appalachian communities, the opposite was seen between low connectivity. It is possible that preventable hospitalization rates could be driving connectivity or vice versa—the study’s cross-sectional design does not allow for determination of directionality. If high rates of preventable hospitalizations are driving connectivity, one might expect to see reductions in preventable hospitalization over time. Future studies should take advantage of longitudinal data to provide further insight into the complexity of the relationship between cross-sector engagement and health outcomes.A recent analysis of longitudinal trends in preventable hospitalizations rates in Kentucky suggests that the gap between rural Appalachian communities and other geographic regions is not closing, despite slight decreases in hospitalization rates.Several limitations should be taken into consideration alongside this analysis. The study is cross-sectional and only measures the association between insurer connectivity and the probability an individual is admitted for a preventable hospitalization. It did not explore longitudinal trends in insurer connectivity and how that might result in changes in preventable hospitalization rates. Examining engagement in community networks and health outcomes. For example, it is possible the direction and strength of relationships in communities might change over time. The study is also limited to a single state: Kentucky. Although the number of Appalachian states with available hospital discharge is limited, building a larger dataset could confirm and increase generalizability of the results.Furthermore, the extent to which insurer market characteristics impact connectivity cannot be determined from these results. Characteristics like market concentration by payer, the number of individuals enrolled in Medicare and Medicaid, and variation in resources put forward by insures may drive connectivity. Additionally, expanding the study to include other states with rural Appalachian communities would help increase understanding of the broader relationship between insurer connectivity in community networks and health outcomes.NALSYS collects data from the local public health official perspective, and not from that of the insurer. While prior studies have found the responses to be reliable and valid, it is possible the data does not capture the full extent of insurer participation in population health networks.Last, this study measures the extent to which insurers play a role as connectors in community networks, but not the specific nature of those relationships. Further research should consider using mixed methods approaches to better understand the characteristics of insurer engagement in community health and social services networks and the mechanisms by which those relationships might improve capacity and health outcomes.Reducing health inequities between rural Appalachian communities and other geographic areas will require bolstering capacity in both clinical and social services systems. This study suggests that high insurer connectivity in cross-sector community health and social services networks may be an important strategy in decreasing preventable hospitalization rates in rural Appalachia. Policymakers should consider how to craft policies and programs to incentivize insurer engagement in population health efforts. Some evidence suggests that such policy change can spur activities to benefit the wider community. For example, changes to IRS nonprofit hospital regulations may be associated with increased involvement in community benefit activities.What is already known about this topic?Integrating health and social services in a community may help to both strengthen the local cross-sector network and ensure a patient’s health and social needs are met, thereby reducing the likelihood an individual experiences an adverse health event. Private sector partners, like insurers, may be able to play a critical role in strengthening community networks in areas with less capacity.What is added by this report?Results from this study suggest substantial geographic variation in the association between greater insurer connectivity in community health / social services networks and the probability of an individual being admitted for a preventable hospitalization. Insurer connectivity in rural Appalachian communities was associated with lower likelihood that an individual was admitted for a preventable hospitalization.What are the implications for future research?Insurer collaboration in cross-sector community networks may be an important strategy in building capacity and reducing the probability of preventable hospitalization in resource-constrained areas like rural Appalachia.