In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations. In the last 15 years, sodium homeostasis has been completely revised going back to concepts that were first introduced in the early 1900s. The discovery of a third compartment in which sodium can accumulate without concurrent water retention is in sharp contrast with the two-compartment model that has been described in medical textbooks since the 1950s  and extracellular compartment 1/3rd) with a similar osmolality. In the intracellular compartment, the main cation is potassium and sodium concentrations are low. The opposite is true for the extracellular compartment where sodium is the main cation and preserves effective circulating volume. According to the two-compartment concept, an increase in sodium intake or hypertonic NaCl infusion will add sodium to the extracellular compartment, increase extracellular osmolality and induce a water shift from the intracellular to the extracellular compartment to control plasma osmolality, which will only slightly increase. Following this increase in plasma osmolality, thirst sensation will lead to increased water intake, and the kidney will retain water in response to antidiuretic hormone release. As a result of a subsequent increase in total body water, plasma osmolality will return to baseline values at the expense of an expanded extracellular fluid volume and rise in blood pressure. This blood pressure increase, in turn, will induce pressure natriuresis and lower total body sodium content. These mechanisms have been first described by Borst and later on by Guyton who both have demonstrated that long-term control of arterial pressure is closely related to body fluid homeostasis [/3rd with/3rd and As outlined above, adopting the traditional two-compartment model implies that the kidney is crucial for regulation of both water and sodium balance and should be perfectly able to match sodium and water excretion with the perceived intake resulting in a ‘zero balance’ during steady-state water and sodium intake. Disruption of this balance will lead to problems with volume or osmoregulation. For example, sodium sensitivity of blood pressure is believed to be attributed to impaired renal sodium excretion.Long-term sodium balance studies, however, have demonstrated that sodium and water homeostasis cannot be explained by the two-compartment model and is more complicated –5. TheseExperimental studies provided an explanation for these unexpected findings. In the skin interstitium, sodium accumulation was associated with increased content and sulfation of negatively charged glycosaminoglycans (GAGs) . Via bininstant intravascular sodium storage. As this vascular system for sodium storage has a volume of 1.5 L in healthy subjects, significant amounts of sodium can be inactivated right after sodium has entered the circulation [In addition to the skin, the endothelial surface layer (ESL) is likely to be involved in nonosmotic sodium storage . The ESLculation . The obsculation –15.The exact role of sodium storage in the skin and ESL and the interaction between both compartments is unknown. We recently hypothesised that skin sodium accumulation, which may seem beneficial at first sight, is harmful and is likely to represent significant sodium excess and impairs vascular function . This isIn clinical practice, physicians need to deal with disturbances of osmoregulation and volume regulation on a daily basis, particularly in subjects with hypertension, kidney disease, or heart failure or critically ill patients. The novel insights into sodium homeostasis may significantly impact daily clinical practice and could provide an explanation for so far inexplicable findings, but may also provide new diagnostic or therapeutic options. We will review the prevalence and importance of (nonosmotic) sodium storage in common diseases and the effect of frequently used therapies and discuss the clinical consequences for dysnatremias, hypertension and sodium intake estimation using urine samples.within a subject may result in different data given the plasticity of the newly discovered third compartment. In the latter case, sodium may be mobilized from interstitial sodium storages in response to hypotonic stimuli, whereas excess sodium may be stored after hypertonic stimuli [The presence of an additional compartment in which sodium can be (temporarily) stored complicates diagnostics and treatments that are based on the two-compartment model. In 1958, Edelman et al. described the relation between serum osmolality and the ratio of total body exchangeable cation content and total body water . On firs stimuli , 24. As The Edelman equation is the basis of formulas that are currently used in daily clinical practice to estimate the effect of sodium or water infusion in case of hypo- or hypernatremia, such as the Adrogue-Madias, Nguyen-Kurtz and Barsoum-Levine formulas –27. HoweData from clinical studies demonstrate that even larger discrepancies are seen in daily clinical practice. Both in hypo- and hypernatremic patients the observed plasma sodium concentrations were > 2 mmol/L higher than expected within 24 h after initiating treatment . In a suTo improve patient care, further research needs to identify factors that affect osmoregulation in addition to total body water, plasma sodium and potassium concentration, and sodium and potassium excretion. This could include patient characteristics that have been demonstrated to affect interstitial sodium storage such as age, gender, sodium intake, blood pressure, diabetes mellitus, infection and inflammation , 33–39. The new insights into sodium homeostasis challenge the (patho)physiology underlying blood pressure regulation and hypertension, in particular the effect of sodium intake on blood pressure, also known as sodium sensitivity. Decades of research have not resolved the phenomenon of sodium sensitivity. This may be explained by the fact that most research was focussed on the kidney as an impaired renal capacity for sodium excretion was thought to be responsible for sodium sensitivity. The findings that total body osmotically active sodium content is not only regulated by the kidney, and that total body sodium content is not necessarily related to blood pressure, provide new insights into potential mechanisms responsible for sodium sensitivity. Recently, interests have shifted to the skin interstitium and ESL as potential modulators of sodium sensitivity , 40.23Na-MRI studies that have demonstrated interstitial sodium accumulation in subjects that are known to be sodium sensitive such as the elderly and hypertensive, diabetic, heart failure and dialysis patients [Laffer et al. have put forward the vasodysfunction theory that links interstitial sodium accumulation with vasodysfunction and ultimately sodium sensitivity . In thispatients –19. Besipatients , 42. Alt23Na-MRI studies show that everyday treatments such as diuretics, sodium glucose cotransporter 2 (SGLT-2) inhibition and dialysis significantly impact interstitial sodium content [Although interstitial storage of sodium is a new, and for many clinicians unknown concept, it is likely that most clinicians have actively altered interstitial sodium content in their patients last month. Data from  content , 18, 43. content . The obsThe novel insights into sodium homeostasis may also lead to new treatment options for hypertension. In this respect, the ESL is of interest as previous studies have demonstrated that the ESL volume in diabetic and chronic kidney disease patients is significantly reduced , 15. ManConsidering the ESL restoring capacity of sulodexide, it increases the intravascular capacity for nonosmotic sodium storage and may thereby decrease osmotically active sodium and potentially blood pressure. To investigate this hypothesis, we have meta-analysed studies that had investigated sulodexide for different medical conditions but also measured blood pressure . In 8 plduring fixed intake because of infradian rhythms in total body sodium content induced by aldosterone and cortisol [A single collection of 24-h urine is regarded as the gold standard for estimation of sodium intake and is widely used in clinical practice and cohort studies. This method is based on the assumption that 24-h sodium intake equals 24-h sodium excretion during stable sodium intake. However, long-term sodium balance studies have shown that this assumption is incorrect as 24-h sodium excretion may be up to 80 mmol different from the actual intake cortisol . On top cortisol . The neecortisol . BaselinThese findings also complicate the use of single urine collections for research purposes. Although a single urine collection can be used for estimation of population sodium intake, individual estimates based on a single urine collection are inaccurate and significantly impact research outcomes. This is illustrated by the abovementioned study that investigated the association between sodium intake and cardiovascular outcome, both when estimating sodium intake with a single baseline collection and when estimating sodium intake with multiple 24-h collections during long-term follow-up . Major dThese novel insights into sodium homeostasis may have potential implications for clinical practice and future research in paediatrics. Studies looking at interstitial sodium storage in children are lacking with most research done in adults. A previous meticulous dietary salt modulation study in healthy girls aged 11–15 of black and white race showed that body sodium retention occurred without weight gain or a rise in blood pressure, raising the possibility that interstitial sodium storage functions in adolescence . In thisThe relevance of the ESL in children has been suggested by a previous study which showed a significant reduction in endothelial glycocalyx thickness by 36% in children with type 1 diabetes compared with controls . This re23Na-MRI could reveal the direction of causality in the relationship between interstitial sodium and blood pressure, showing if interstitial sodium accumulation starts early in life and precedes, or is implicated in the development of hypertension. This may further strengthen the need for preventative strategies such as dietary sodium reduction in children to prevent the onset of hypertension in adulthood. Recent studies have shown a higher prevalence of sodium sensitivity in women with possible differences in interstitial sodium accumulation and storage [The association between sodium intake and blood pressure in children has been previously reviewed . As in a storage , 35, 60.Interstitial and ESL sodium storage is a clinically relevant concept that complicates treatments and diagnostics based on the classical two-compartment model but may also provide new possibilities for treatment of common diseases such as hypertension. The current understanding of the impact of (nonosmotic) sodium storage on daily clinical practice is likely to be only a fraction of the impact it actually has.


Thus, lateral inhibition is conditional on activity in the principal neurons connected to a granule cell and tightly intertwined with recurrent inhibition. This notion allows us to infer that lateral inhibition between principal neurons occurs “on demand,” i.e., selectively on coactive mitral and tufted cells, and thus can provide directed, dynamically switched lateral inhibition in a sensory system with 1000 input channels organized in glomerular columns. The mechanistic underpinnings of this hypothesis concur with findings from odor discrimination behavior in mice with synaptic proteins deleted in granule cells. In summary, our hypothesis explains the unusual microcircuit of the granule cell reciprocal spine as a means of olfactory combinatorial coding.The role of granule cells in olfactory processing is surrounded by several enigmatic observations, such as the purpose of reciprocal spines and the mechanisms for GABA release, the apparently low firing activity and recurrent inhibitory drive of granule cells, the missing proof for functional reciprocal connectivity, and the apparently negligible contribution to lateral inhibition. Here, we summarize recent results with regard to both the mechanisms of GABA release and the behavioral relevance of granule cell activity during odor discrimination. We outline a novel hypothesis that has the potential to resolve most of these enigmas and allows further predictions on the function of granule cells in odor processing. Briefly, recent findings imply that GABA release from the reciprocal spine requires a local spine action potential and the cooperative action of NMDA receptors and high voltage-activated Ca The role of granule cells in olfactory processing is surrounded by several enigmatic findings  in more detail, odorant molecules bind to olfactory receptor neurons in the nasal epithelium. The axons of these receptor neurons terminate in glomeruli of the olfactory bulb (OB) where they interact with local interneurons and the apical dendritic tufts of the bulbar projection neurons, the mitral and tufted cells (MTC), which in turn send their axons mostly to olfactory cortical areas  recurrent inhibition, which refers to interneuron feedback onto an exciting MTC, and (2) lateral inhibition, which refers to interneuron feedforward onto MTCs other than the exciting MTC. GCs, the most numerous neuron population of the OB, participate in both recurrent and lateral inhibition of MTCs at the level of the EPL, where they receive glutamatergic synaptic input from MTC lateral dendrites which they provide with reciprocal GABAergic output. Axonless GCs feature basal dendrites and an apical dendrite, both spinous, with the apical dendrite extending from the granule cell layer (GCL) into the EPL and contacting MTC lateral dendrites via large spines that house the reciprocal synapses , but did not provide data for an involvement of voltage-gated Na+ (NaV) channels as in “classical” axonal release  in MTCs, the recurrent rIPSPs were strongly reduced. These results demonstrated that an AP was required for GABA release at the reciprocal synapse, just like neurotransmitter release from regular axonal presynaptic terminals  that in turn activate HVACCs. This mechanism relies on the tight electrical isolation of the spine head by the high spine neck resistance, boosting the AMPAR-mediated EPSP  a rapid relief of Mg2+ block  during the repolarization phase of the AP, the driving force for Ca2+ entry through HVACCs will strongly increase SPINE will closely resemble that of the spine spike  unitary release upon single MTC input; (2) the same spine was already activated within the NMDAR memory time window and the subsequent glutamate release generates recurrent inhibition as described above, e.g., during a theta burst of an MTC; (3) the GC fires an action potential that enters all spines , but GABA is only released from those spines that were activated during the NMDAR memory time window, thereby generating lateral inhibition. In essence, short MTC bursts will facilitate recurrent inhibition and lateral inhibition will mostly affect MTCs that are currently active or were active very recently.r_GABA from spiking GCs remains in the absence of glutamate, which is then amplified by the large number of stimulated GCs. Alternatively, the stimulation activates other, yet unknown inhibitory inputs to MCs, e.g., from deep short-axon cells or axons of EPL interneurons  The involved GCs have to be excited sufficiently to generate a non-local spike  or global spike. Evidence for global GC spiking upon uniglomerular activation in vitro has been observed by several groups, including our own  Moreover, because of the necessary activation of the NMDARs in the GABAergic active zone, there will be only little GC-mediated lateral inhibition upon activation of a single column because there is no glutamate provided at the lateral spines  to enhance recurrent inhibition. Non-topographical lateral interactions in the bulb have been proposed already previously by others based on functional evidence and simulations  by Arevian et al. ; one “seActivity dependence is also reflected in the labeling of glomerular columns spanning all layers of the bulb by markers of neuronal activity  of the apical dendrite or involve local dendritic spikes and will therefore not be visible to recordings from the GC soma. Furthermore, this spiking activity may also remain undetected in field potential recordings, because the limited space within which currents will flow might not suffice to generate sources and sinks far enough apart to be detected. In our view, global spikes mostly serve to enhance (but not trigger) a GC’s output across coactive columns.GCs do not prevent MC spiking but influence MC spiking frequency and therewith could contribute to the synchronization of coactive columns. In this scenario, recurrent inhibition is inherently linked to lateral inhibition.According to the model proposed here, lateral inhibition does exist, but predominantly between coactive columns and always in combination with recurrent inhibition, making it easy to miss experimentally.V1.2 subunit in mouse GCs, consistently affected odor discrimination time, such that manipulations that both should reduce GABA release  result in decreased recurrent inhibition and a slowed odor discrimination. Conversely, the GluA2 KO manipulation should increase GABA release  and indeed increased recurrent inhibition and accelerated odor discrimination. Since according to our hypothesis lateral inhibition is tightly related to recurrent inhibition, it is likely to be affected in a similar manner. Hence, our framework is further closing the loop from molecules to synapses, networks, and behavior in olfactory bulb function.Manipulations of essential components of the reciprocal microcircuit, i.e., deletion of the glutamate receptor subunits GluA2 or GluN1 and knockdown of the sodium channel Na


The purpose of this paper is to report the baseline characteristics of EMPOWER participants—a group of newly diagnosed breast cancer survivors—and describe differences in hourly and salaried wage women’s experiences regarding cancer and work management in the three months following breast cancer diagnosis.The EMployment and Potential Outcomes of Working through canceER (EMPOWER) project is a prospective longitudinal, mixed methods pilot study designed to evaluate how employment influences treatment decisions among women diagnosed with breast cancer. Participants were women diagnosed with new breast cancer and treated at one of two clinical sites of the University of Maryland Medical System. Women were enrolled in the study within three months of first breast cancer diagnosis. Study visits occurred every three months for one year. This paper reports data from for the baseline and three-month visit which had been completed by all enrollees.Trained research personnel collected demographic information, medical history and health status, social history, employment data, cancer-related data, psychosocial adjustment, and financial wellbeing at the baseline enrollment visit. A semi-structured qualitative interview was administered at the three-month study visit to assess employment decisions and the impact of job demands, cancer care, and cancer-work fit during the three months following diagnosis.Fifty women with new, primary diagnosis of breast cancer were enrolled in the study. Mean age of participants was 51 years, and 46% identified their race as Black or other. The majority of women disclosed their diagnosis to their employer and nearly all maintained some level of employment during the first three to six months of treatment. Women with hourly wage jobs were similar to those with salaried wage jobs with respect to demographic and social characteristics. Women with hourly wage jobs were more likely to report working in physically demanding jobs and taking unpaid leave. They were also more likely to experience side effects that required physical restrictions at work, to leave their jobs due to demands of treatment, and to report managing cancer and work concurrently as very difficult. Women in salaried wage jobs were more likely to report falling behind or missing work and working remotely as a cancer-management strategy. Women in hourly jobs more often reported difficulty managing the competing demands of cancer and work.While further study is needed, these results suggest that women in hourly and salaried workers reported similar experiences managing cancer and work, with a few key exceptions. These exceptions pertain to the nature of hourly-wage work. Cancer survivors employed in hourly jobs may be more vulnerable to poor employment outcomes due to limited access to paid time off and workplace flexibility, and challenges related to managing physical aspects of cancer and employment. Improvements in cancer screening and early detection in recent decades have increased 5-year survival across cancers by 70%  and led while receiving treatment. Optimal management of cancer care and employment during active treatment may be influenced by features of the cancer care experience, employment needs and characteristics, or both.Much of the extant literature has focused on return to work and factors related to cancer survivors’ ability to successfully return to work following diagnosis and treatment. In systematic reviews, Van Muijen and colleagues  and MehnSwanberg et al, 2020  recentlyThis study was reviewed and approved by the University of Maryland Baltimore Institutional Review Board (IRB), the University of Maryland’s Greenebaum Comprehensive Cancer Center’s Research Committee, and the Research Committee of the University of Maryland St. Joseph’s Medical Center. All participants provided written consent to participate in the study.The data reported herein were collected as part of the EMployment and Potential Outcomes of Working through cancER project. The EMPOWER project is a longitudinal, mixed methods  pilot study designed to evaluate how employment influences treatment decisions among women diagnosed with breast cancer. A consecutive series of women with new breast cancer diagnosis (N = 50) were recruited from the University of Maryland’s Greenebaum Comprehensive Cancer Center (UMGCCC) and the University of Maryland St. Joseph’s Medical Center (UMSJMC) between July 2017 and October 2018. Women were eligible for participation if: 1) female; 2) 18 years or older; 3) they had been diagnosed with new, primary breast cancer within three months of enrollment (stages 0–4); 4) were employed at least 20 hours per week at the time of diagnosis; and 5) were able to read, speak, and understand English in order to provide informed consent and complete study procedures. Participation in the EMPOWER Study includes completion of study visits at five time points: baseline–which was within three months of being diagnosed with cancer, and then subsequently every three months for four additional visits. For the purpose of this study, we report results from the enrollment visit (visit 1) during which the interviewer assisted survey data were collected, and the qualitative interview conducted at visit 2. Women received compensation for completion of each study visit.Potentially eligible women were identified through daily review of the electronic health records of UMGCCC and UMSJMC to identify women with new diagnosis of breast cancer. Diagnosis was confirmed with the respective cancer treatment team, and eligible women were sent a letter of invitation to participate in the study. Trained research staff contacted eligible women to explore interest in participation and to confirm employment status at the time of diagnosis. Women who were interested in participation were scheduled for an enrollment visit during which informed consent and completion of the baseline data collection occurred.Trained research personnel collected demographic information, medical history and health status, social history, employment data, cancer-related data, psychosocial adjustment, and financial wellbeing at the baseline visit using an instrument comprised of measures described in more detail below. Quantitative data for the baseline survey were collected via a face-to-face interview-assisted survey method around the time of a medical appointment at the UMGCCC. Interviewers trained to conduct qualitative interviews conducted semi-structured qualitative interviews at the three-month visit to assess participants’ decisions related to continued employment, disclosure of cancer diagnosis to people at work, and workplace factors that influenced survivors’ employment decisions. Qualitative interviews were conducted over the telephone. No research personnel were involved in clinical care of participants.Demographics. A structured demographics questionnaire collected information regarding age, race and ethnicity, sex, education, income, housing status, insurance data.Social history. Social history data included marital/partner status, presence of children under the age of 18 living in the household, caregiver status, household size.Medical and health history. Medical and health history data were collected from each participant’s electronic health record and by self-report. Medical and health history data included cancer diagnosis data  comorbidities, and tobacco and substance use history.Employment characteristics. Self-report employment data included employment status, changes in employment, job characteristics , length of employment, employment sector, and whether typical shift worked.Disclosure to employer. Participants were asked a series of questions to determine the extent to which they had disclosed their breast cancer diagnosis at work. Questions addressed disclosure to co-workers, managers, and human resources personnel at the employer.Workplace supports, adjustments, and challenges. Women were asked to provide information about resources  that were available to them through their employers to help them manage breast cancer diagnosis and treatment while continuing to work. Questions from the Medical Expenditures Panel Cancer Self-Administered Questionnaire (MEPS-CSAQ)  to characterize the sample and scores on quantitative measures. Mean(SD) are presented for continuous variables and percentage(n) are presented for categorical variables. Fisher’s exact tests were used to examine differences on categorical variables, while Student’s t-tests were used to assess differences on continuous variables. Analyses were performed using Stata 15 SE . Given the pilot nature of this study and small group sizes, we report obtained p-values ≤0.10.Qualitative data analyses. Qualitative data were transcribed and coded by trained research personnel to identify themes. Our approach to qualitative coding was a combination of framework analysis based on the Cancer-work Management Framework  defined as those who reported incomes of 200% of the U.S. federal poverty guideline, and women who were hourly wage workers were significantly more likely to meet the definition for working poor. Approximately, 14 percent of women reported high financial distress in the period between enrollment and the 3-month visit; no differences in financial distress were noted between hourly and salaried wage workers. However, it is noteworthy that hourly wage workers were more likely than salaried workers to skip this question during the survey and that among those who answered it, 21% reported high financial distress, compared to 9% among salaried workers.unpaid time off. Few women made changes to their job duties as a result of cancer diagnosis. In general, women rated overall quality of support from their employer for managing cancer-work challenges as good to high support.Nearly all participants (92%) disclosed their breast cancer diagnosis to someone  in the workplace, and no differences in disclosure were noted between hourly and salaried wage workers. With respect to workplace supports and adjustments  a majority took either paid (44%) or unpaid (26%) time off for treatment and/or its side effects; hourly wage women were significantly more likely to have taken A notable number of women reported that cancer treatment created workplace challenges that needed to be managed. Across all participants, 39% reported that cancer treatment made it difficult to keep pace with others/coworkers; 37% felt cancer treatment led to decreased work productivity; 33% felt treatment interfered with the ability to perform physical tasks required by their job; and 35% believed cancer treatment interfered with their ability to perform mental tasks required by their job. No differences were noted in the pattern of workplace challenges experienced by hourly wage workers compared to salaried workers.No participants reported deciding not to get recommended treatment due to cancer-work management conflicts; however, a small minority (8%) reported a change in the length of time (schedule) of treatment to accommodate work needs. Hourly wage women were more likely to report that they would have to make financial sacrifices as a result of cancer-work management issues . Hourly wage workers were significantly more likely to be receiving financial assistance (p<0.01).Women implemented a number of cancer-work fit strategies as a way to incorporate cancer care into their work life routines. These cancer-work fit strategies were categorized into workplace strategies and cancer care strategies see . WorkplaWomen with hourly and salary jobs had several different cancer-work management experiences see . With reThe current study is one of the first the authors are aware of to characterize breast cancer survivors’ cancer-work management during active cancer treatment. The objective of this paper is to report the baseline characteristics of EMPOWER participants and to describe differences in hourly and salaried women’s choices regarding cancer-work management during the three months following new breast cancer diagnosis. During the first three months of treatment women must abruptly adjust to the psychological implications of receiving a cancer diagnosis, while also adjusting their work, personal and family lives to accommodate cancer care. Nearly all survivors enrolled in this study maintained employment during the first three to six months of treatment. Similar to what is observed for the general employed population , women wNearly all participants disclosed their breast cancer diagnosis to their employer and/or coworkers. Seventy percent of participants took time off work for treatment or because of treatment side effects; 26% took unpaid time off, and survivors in hourly wage positions were more likely to take unpaid time off than their salaried wage counterparts. Women with hourly jobs were also somewhat more likely to report that cancer management interfered with their ability to perform physical aspects of their jobs. Both hourly and salaried wage breast cancer survivors generally felt they had access to adequate workplace supports and accommodations and that their workplace supported the need for flexibility of schedules in order to manage cancer and work. It is noteworthy, however, that women with hourly jobs were significantly more likely to need to make physical accommodations on their jobs in response to cancer care demands, to leave their jobs altogether due to the demands of treatment, and to express that managing cancer-work fit was very difficult. This is in contrast to women in salaried jobs who were more likely to share that they were able to work remotely as a strategy for maintaining employment during active treatment.Results from the qualitative portion of this study illuminate aspects of the Cancer-work Management Framework  and provThe cancer care delivery system was another important factor in women’s strategies for cancer-work management. The timing and frequency of appointments, as well as the proximity of the cancer care center contributed to women’s decision to continue to work, whether they needed to take time off and for how long, and ultimately if they would need to take extended leave or resign from their job. Providers often communicate directly and indirectly that treatment should be prioritized above all else; in reality, cancer survivors have rich lives filled with competing joys and responsibilities that create complex cancer-management scenarios that are seldom as simple as “treatment comes first.” Cancer care providers’ awareness and concern about women’s jobs also played a role in many of the participants cancer-management experiences. Offering early morning appointments or appointment times that did not conflict with women’s work schedules eased concerns about missing work or needing to take leave. Similarly, switching to care locations proximal to home or work allowed women to minimize their time away from work thus easing the ability to remain employed while receiving cancer care.Our study operationalizes job and cancer demands experienced by working breast cancer survivors during active treatment. and the strategies used to manage the cancer-work interface. In reality it is the intersection of all of these experienced demands and readily accessible resources and supports available to women at work and through their treatment team that influence women’s decisions about how they navigate treatment while working. Given that a majority of our participants wanted or needed to continue working while receiving cancer care, cancer care teams should consider ways in which they can engage collaboratively with survivors to develop treatment decisions and plans in ways that support continued employment if that is a priority for the survivor.While cancer-work management is challenging for any cancer survivor, results from this study suggest the occupational conditions inherent to hourly jobs may influence women to make decisions that could influence financial stress and well-being, long-term employment, and job security. The longitudinal design of the EMPOWER study will allow researchers to examine the associations between job conditions and outcomes over time.The current study offers new insights related to how hourly and salaried wage women manage employment decisions following new breast cancer diagnosis. Even so, our study had several limitations that should be acknowledged. First, categorizing occupations into binary categories does not take into account variation in job conditions that may exist within the hourly and salary categories. However, we opted to use these categories because we wanted to understand the experiences of workers in jobs that frequently have few employer-based resources with those workers who may be more likely to have employer-sponsored resources to assist with cancer-work management. Hourly work is a term that is synonymous with low-wage work, and salaried jobs are typically thought of as jobs that come with standard employee benefits and are these job classifications are frequently used by other researchers , 12. SecHourly wage women in our study were somewhat more likely than salaried wage women to report challenges managing cancer and work. This included needing to take more unpaid time off in order to meet the demands of treatment, having lack of flexible work arrangements, needing to make modifications  to physical aspects of their jobs, and reporting that managing work and cancer treatment was very difficult. Hourly wage women were also more likely than their salaried counterparts to leave their jobs altogether due to the demands of cancer treatment. Our study is the first we are aware of to examine differences in cancer-work management by job type–hourly vs salary. The differences that emerge indicate that at least at the beginning of treatment, the types of workplace supports that are beneficial differs between the two groups. Because hourly wage women were more likely to take unpaid time off and leave their job altogether, cancer treatment may put this group at a higher risk of financial stress over the course of treatment.Future research is needed to better understand the influence of occupational conditions on employment and cancer decision making of breast cancer survivors, financial stress and well-being, and employment outcomes. This study sets the foundation for future multi-variate analysis to examine direct and in-direct effect of job conditions on these stated outcomes. Data from the EMPOWER study will allow for this type of exploration and possibly form the basis for a larger study of cancer-work management among breast cancer patients in hourly and salary jobs. Likewise, understanding the interplay between the physical demands of cancer treatment, job conditions, and other factors that influence cancer-work management (e.g. provider supports) could help to identify key areas for interventions that might ease challenges experienced by survivors managing cancer and work.


Prenatal exposure to an adverse uterine environment can have long lasting effects on adult offspring through DNA methylation, histone acetylation, and other epigenetic effects that alter gene expression and physiology. It is well-known that consumption of CNS stimulants such as caffeine, nicotine, amphetamines, and cocaine during pregnancy can adversely impact the offspring. However, most work in this area has focused on neurological and behavioral outcomes and has been limited to assessments in young offspring. The impact of prenatal exposure to these agents on the adult cardiovascular system has received relatively little attention. Evidence from both animal and human studies indicate that exposure to CNS stimulants during the gestational period can negatively impact the adult heart and vasculature, potentially leading to cardiovascular diseases later in life. This review discusses our current understanding of the impact of prenatal exposure to cocaine, methamphetamine, nicotine, and caffeine on the adult cardiovascular system. Drug and alcohol use during pregnancy is a significant public health concern. The 2018 National Survey on Drug Use and Health estimated that 5 % of pregnant women used an illicit drug within the past month , the strThe premise of the “developmental origins of adult health and disease” (DOAHD) hypothesis, originally proposed by de Boo and Harding , is thatCocaine increases adrenergic, dopaminergic, and serotonergic signaling in the CNS and peripheral organs by blocking the removal of norepinephrine, dopamine, and serotonin from the synapse through their respective transporters. Maternal cocaine use acutely increases blood pressure, heart rate, and catecholamine levels in both the mother and the fetus , and thePrenatal exposure to cocaine also alters adult vascular function. Xiao et al.  found thPrenatal cocaine also disrupts the function of the adult coronary vasculature. Coronary microvessels constrict and dilate in response to changes in luminal pressure. These pressure-induced changes in myogenic tone provide an important mechanism for the autoregulation of blood flow within the myocardium , 36. HowStudies of blood pressure in humans that were prenatally exposed to cocaine are sparse and have produced mixed results. Some investigators have reported elevated blood pressure in children following prenatal exposure to cocaine , 40, whiThe Infant Development, Environment, and Lifestyle (IDEAL) study estimated that 5% of pregnant women used methamphetamine at some point during their pregnancy . UnfortuMethamphetamine and cocaine differ in their mechanisms of action, but both agents produce similar physiological effects that are mediated by increased adrenergic and dopaminergic signaling. Thus, it is not surprising that prenatal exposure to methamphetamine produce outcomes in the hearts of adult offspring that are similar to those observed following prenatal exposure to cocaine. Our laboratory found that adult rats that were prenatally exposed to methamphetamine develop myocardial hypersensitivity to ischemia . SimilarIt is unclear why fetal exposure to methamphetamine produces sex dependent effects in the hearts of adult offspring. Shen et al.  reportedCigarette smoking has dramatically decreased in the United States since reaching its peak in the 1950s . HoweverHuman studies assessing blood pressure in children born to mothers who used tobacco while pregnant have produced mixed results. Some investigators have found elevated blood pressure in these children –67 whileAnimal studies indicate that prenatal nicotine exposure also produces long term effects on the heart. Lawrence et al.  found thCaffeine is the most commonly consumed CNS stimulant in the United States. Caffeine is consumed by 89 % of the US population  on any given day . ImportaAnimal studies indicate that caffeine exposure during the prenatal period induces epigenetic changes in gene expression that result in cardiac hypertrophy  in adult offspring –86. WendAnimals studies indicate that prenatal caffeine also alters vascular function in adult offspring. Serapiao-Moraes  reportedIn addition to its effects on contractile function, prenatal caffeine may also increase the risk of cardiovascular disease by promoting hypercholesterolemia. Guo et al. reported that adult rats that had been prenatally exposed to caffeine had increases in total cholesterol, low density lipoproteins (LDL), and apolipoprotein B expression following prenatal exposure to caffeine. These animals also had suppressed high density lipoprotein (HDL) and decreased expression of LDL receptors . These cWidespread dietary consumption of caffeine makes it difficult to investigate the impact of prenatal caffeine on adult cardiovascular function in humans. We are unaware of any studies that have assessed the impact of maternal caffeine consumption on blood pressure, cardiac physiology, blood lipid profiles, or other cardiovascular parameters in human offspring. The widespread consumption of caffeine, prevalence of cardiovascular disease, and evidence of negative cardiovascular outcomes in animal models warrants further investigation to assess the potential long-term cardiovascular risks of prenatal caffeine exposure in humans.Despite having different molecular targets, CNS stimulants share some common effects on the fetus that may explain the mechanism by which they adversely impact the adult heart. Maternal use of cocaine , methampThe ability of CNS stimulants to disrupt sleep is well-established. Disruption of sleep patterns and alterations in the circadian rhythm increase myocardial sensitivity to ischemia in rodents , 102 andMultiple studies have established a correlation between low birth weight and increased risk of cardiovascular diseases during adulthood –107. TheFetal exposure to CNS stimulants can have a variety of negative cardiovascular consequences that extend into adulthood . HoweverPolydrug use is common among both illicit drug users as well as those who consume tobacco products and dietary caffeine. Previous studies have demonstrated that smokers drink more coffee than non-smokers and that tobacco and coffee consumption tend to occur simultaneously –118. A sAnimal studies provide evidence that fetal exposure to CNS stimulants leads to changes in the expression of protein kinase C-ε , 32, 73,It is unclear whether the cardiovascular effects that have been observed in adult offspring following prenatal exposure to CNS stimulants result from a direct effect of these drugs on the developing heart and vasculature or if they are secondary to stimulant-induced changes in the CNS. Previous work has demonstrated that prenatal exposure to cocaine , nicotinIn conclusion, there is growing evidence that fetal exposure to cocaine, methamphetamine, nicotine, and caffeine negatively impact the heart and vasculature through a variety of mechanisms that may lead to an increased risk of developing cardiovascular disease during adulthood . Our undThis manuscript was written by BR.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute kidney injury (AKI) is a threatening medical condition associated with poor outcomes at different settings. The development of standardized diagnostic criteria and new biomarkers addressed significant clinical impacts of AKI and the need for an early AKI detection, respectively. There have been some breakthroughs in understanding the pathogenesis of AKI through basic research; however, treatments against AKI aside from renal replacement therapy (RRT) have not shown adequate successful results. Biomarkers that could identify good responders to certain treatment are expected to facilitate translation of basic research findings. Most patients with severe AKI treated with RRT died due to multiple-organ failure, not renal dysfunction. Hence, it is essential to identify other organ dysfunctions induced by AKI as organ crosstalk. Also, a multidisciplinary approach of critical care nephrology is needed to evaluate a complex organ crosstalk in AKI. For disruptive innovation for AKI, we further explore these new aspects of AKI, which previously were considered outside the scope of nephrology. Acute kidney injury (AKI) is characterized by an acute decline in renal function. Since the concept of AKI was suggested by addressing the importance of early detection and early intervention around 2004–2005 , 2, manyThe Kidney Disease Improving Global Outcomes (KDIGO) criteria were published in 2012 and is currently the international gold standard of AKI diagnosis . The KDIThe KDIGO criteria defined AKI as an increase in the serum creatinine and a reduction in the urine output. It is well known that an increase in serum creatinine delays glomerular filtration rate (GFR) reduction for 24–48 h . To overThe KDIGO criteria determines AKI severity by serum creatinine elevation and urine output. The Japanese AKI guideline  indicateTwo common clinical markers of serum creatinine and urine output, which are used by AKI diagnosis with the KDIGO criteria, have several serious disadvantages as described above. This promoted to develop better diagnostic tools for AKI and several new AKI biomarkers were investigated for the last decade.Although AKI is a syndrome associated with a broad spectrum of diseases and a variety of underlying etiologies, two distinct phenotypes need to be assessed in clinical settings: transient  AKI and persistent  AKI. Transient AKI can be categorized as a fluid-responsive AKI as correction of renal perfusion by fluid resuscitation will rapidly improve renal function in transient AKI patients. In several different clinical conditions, the prognosis of transient AKI was reportedly better than persistent AKI –25. PersEspecially in ICUs, the common underlying etiology of persistent AKI is acute tubular injury. Detecting tubular epithelial injury helps in distinguishing persistent from transient AKI. The fractional excretion of sodium (FeNa) and urea (FeUN) are widely used; however, their effectiveness is inadequate especially in sepsis , 27. FurIn cancer screening, five consecutive phases of biomarker development were proposed . The finEarly detection of AKI seemed to be the main purpose for new AKI biomarker development; however, other purposes such as predicting fluid responsiveness  and identifying responders to certain treatments need to be emphasized for clinical applications.As abovementioned, no clinically available drug can prevent or treat AKI. A number of potential effective treatments in basic research with animal models failed to be translated for clinical application. It has been pointed out that the failure to translate results from basic research to clinical practice is due to complex and heterogeneous disease characteristics of AKI, inappropriate designs of clinical trials , and irrelevant animal models that insufficiently mimic human AKI .The need for clinically relevant animal models in the preclinical study has been addressed , 49. SepCecal ligation and puncture (CLP) is another animal model showing a ligation distal to the ileocecal valve and a needle puncture of the ligated cecum that causes fecal material to leak into the peritoneum, resulting in poly-microbial bacteremia and sepsis . SupportAnimal models should mimic human AKI in as many aspects as possible, including the pace and severity of disease, renal hemodynamic changes, histological findings, and immunological responses. The use of bigger animals such as sheep and pigs may be applicable to mimic the human ICU environment, especially in the later phase of drug development. More fundamentally, to develop AKI models of higher clinical relevance, other factors that should be mimicked must be considered. Due to a very limited number of renal biopsies occurring in human AKI, actual mechanisms of disease and drug targets for human AKI could be overlooked. Of note, the Kidney Precision Medicine Project (KPMP), funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), is trying to obtain kidney biopsy samples from AKI patients to better characterize human AKI .Basic research is undoubtedly necessary to develop clinically effective treatments against AKI. One-way translation of from bench-to-clinical approach seemed not to be effective so far. Bedside-to-bench-to-bedside approach will enable to improve animal models in basic research and promote drug development in the clinical.When potentially fatal changes in the body fluid, electrolyte, and acid–base balance occur, renal replacement therapy (RRT) is an effective treatment for severe AKI. Because of the remarkable progress in RRT, hemodynamically unstable patients in the ICU may be treated with continuous RRT (CRRT) or sustained low-efficiency dialysis (SLED) , 64. DatⓇ were evaluated in the clinical settings . Fo. Fo83]. New concepts of AKI and standardized diagnosis criteria helped us to determine a considerable impact of AKI on clinical outcomes and the need for early detection and early intervention. New biomarkers are a more useful tool in monitoring renal injury in AKI compared with serum creatinine and urine output. However, a better tool for therapeutics against AKI remains unknown. How can we make a breakthrough in this situation? The term of “disruptive innovation” was defined and first analyzed in 1995 by the American scholar Clayton M. Christensen . A disruExtracellular histones and neutrophil extracellular traps (NETs) are one of the potential targets in other organ injuries in AKI. Extracellular histones induce cytotoxicity triggering the inflammatory cascade via toll-like receptors. They are released from neutrophils during the NETs formation. In a mouse intestinal ischemia–reperfusion model, we observed extracellular histone accumulation and NETs formation in the liver rather than intestine . ExtraceIn conclusion, AKI is one of the most serious diseases that show unacceptably high mortality and no specific drug can sufficiently prevent and treat AKI in the clinical. We need to be aware that AKI is not a self-limited kidney disease but a syndrome with wide disease spectrum mostly complicated with systemically ill patients. On the other hand, many basic researches especially focusing on organ crosstalk in AKI have found new mechanisms. Hopefully, a multidisciplinary approach of critical care nephrology and remote organ injury evaluation in AKI will lead to new directions for future AKI research.


Assessing and addressing patient histories of trauma constitute a critical component of care for vulnerable populations such as pregnant patients, yet they often go unrecognized in obstetric care. Obstetric providers may feel poorly equipped to address this issue comfortably and effectively.We designed this didactic module for obstetric residents with previous experience taking patient histories and delivering clinical care. The module was delivered with a faculty member and three additional facilitators with expertise in communication skills training. The session included 60 minutes of background information followed by a 15-minute presentation of a communication template for assessing trauma history. Using a practice case, residents had 45 minutes to practice in small groups, with the facilitators serving as the patient in the role-play.In the 2015-2016 academic year, 21 obstetric residents participated in this module. All residents (100%) endorsed favorable beliefs regarding the importance of assessing trauma history and using trauma-informed care. On average, three-fourths (77%) demonstrated basic awareness of issues related to trauma in medical populations. Most residents (>85%) reported a high sense of efficacy in delivering trauma-informed care in some areas, while fewer (64%) reported efficacy specifically in educating patients about signs and symptoms of traumatic stress.The module was well received overall, with participants indicating that clinical training in trauma-informed communication was needed to enhance their sense of efficacy in this area. This learning exercise provided training in a critical communication skill while highlighting areas for further development. Moreover, in order to fully appreciate how historical traumatic experiences can exert ongoing adverse effects on the health of pregnant women and their developing fetuses, trauma-informed communication must capture more than just acute crises such as current intimate partner violence.11Some curricula exist to fill gaps in communication training related to patients experiencing pregnancy complications and difficult topics such as pregnancy loss.6 and the Substance Abuse and Mental Health Services Administration guide to trauma-informed care for guidance and consultation.12Thus, this module has been developed to provide background knowledge on the potential adverse effects of traumatic stress on pregnancy outcomes as well as a structured, empirically supported framework for taking a trauma history and responding effectively and empathically to disclosures of trauma. This activity is intentionally targeted toward OB/GYN residents to provide them with a safe learning environment in which to practice skills that they can immediately apply to their day-to-day clinical environments in the management of obstetric patients. Although specific instructions for how to implement principles and practices of trauma-informed care are beyond the scope of the module, references in it . Thus, the framework reduces the likelihood of false-negative responses to the screening while also minimizing stigma associated with experiences of sexual violence. The standardized role-play exercise is designed to provide the opportunity to practice empathic communication utilizing these behaviorally anchored phrases.The framework for taking the patient's trauma history and responding to disclosures has been developed using empirically supported approaches.We designed this module for OB/GYN residents at any year of residency. The existing residency curriculum at our institution included didactic lectures on mental health screening and medical management of depression during the perinatal period. However, the curriculum did not include advanced communication skills training in mental health, traumatic stress, or trauma-informed care. Residents were expected to have a basic knowledge of mental health issues affecting the perinatal period but no prior knowledge specifically about trauma. Therefore, this module and its standardized role-play exercise were designed to serve as an introduction to communication with pregnant patients having histories of trauma and possibly also active symptoms of traumatic stress.Facilitators for this module included one faculty leader and three instructors in behavioral sciences. The faculty leader, a clinical psychologist, had 5 years of clinical experience in the assessment and treatment of trauma-related disorders in perinatal populations as well as 4 years of experience teaching as part of an advanced communication skills curriculum for medical students. The three instructors were clinical psychology postdoctoral fellows in the process of completing a 2-year postdoctoral fellowship in traumatic stress and women's health psychology. One of the instructors also taught in the advanced communication skills curriculum for medical students. Thus, all facilitators had background in the screening, assessment, and psychological treatment of trauma-related disorders in perinatal populations, and two of the four had experience teaching communication skills to medical trainees.Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for post-traumatic stress disorder (PTSD), empirically supported methods for assessing and responding to trauma histories, and case material development for the role-play exercise. Facilitators met as a group with the faculty leader to construct the didactic module, develop the case materials, and rehearse the role-play exercise.Facilitators participated in the development of module materials, including collecting scientific literature on traumatic stress and pregnancy, The faculty leader also provided training to facilitators in offering feedback to OB/GYN residents when they participated in the standardized case role-play. Feedback training covered providing specific behavioral examples of effective versus less-effective communication around the topic of trauma and addressing and providing support for discomfort/distress residents might encounter upon practicing these skills. As clinical psychologists, facilitators were encouraged to utilize their expertise when addressing residents’ discomfort or significant distress.For our OB/GYN program, each class (by year) contained six residents, for a total of 24 residents. Rather than delivering the module to each class separately, we opted to deliver it to the entire program of 24 residents. This saved time while also allowing more-senior residents to share their experiences and expertise with first- and second-year residents. The module was delivered as a onetime stand-alone didactic over 2 hours. The classroom space utilized was a traditional classroom setting where the residents’ didactics usually took place, with desks and chairs for 24 residents as well as the space to break out into small groups for the standardized case role-play exercise. Thus, the classroom needed to be large enough for the group of 24 residents to be comfortably divided into groups of four to five participants, with enough distance between the small groups so that they did not distract each other.•7:30 am-8:30 am: background, didactics, and discussion in the full group of 24 residents.•8:30 am-8:45 am: presentation of communication template for taking the trauma history.•8:45 am-9:30 am: small-group practice (four to five residents) with a designated person serving as the patient  followed by wrap-up.The didactic module was designed to last 2 hours on the following schedule:Necessary equipment included a projector and screen for the didactic portion of the module.•Didactic facilitator guide .•PowerPoint slides  for back•Handout 1: sample chart of a pregnant patient with PTSD .•Handout 2: communication template for taking a trauma history .•Handout 3: sample trauma-informed practice .•Handout 4: sample trauma narrative for the role-play .•Pocket guide for trauma history screening .The following documents were needed for the didactic portion and the standardized case role-play portion of the module:16 Following the discussion of barriers, facilitators presented and described the communication template for taking a trauma history and responding to disclosures. The communication template formed the basis for the role-play exercise in which residents had the opportunity to put communication skills into practice.This module was delivered to 21 OB/GYN residents (three residents were absent that day) in academic year 2016-2017. Four facilitators  conducted the didactic module following the facilitator guide , PowerPoThe four facilitators then led the role-play exercise. All residents participated in the role-play exercise in groups of four or five, with one facilitator serving as the patient using the sample trauma narrative . In smalThe standardized case role-play exercise was conducted using a round-robin interview style whereby each resident took turns assessing the patient's trauma history and responding to the patient's answers. Residents were expected to engage in this exercise using the sample trauma-informed phrases and responses, which communicated empathy, sensitivity, and nonjudgmental acceptance of the patient's history. Facilitators provided on-the-spot feedback to residents and led the small groups in a brief discussion of what aspects of the interview went well and what aspects were most challenging for residents. Residents were encouraged to offer one another constructive feedback, with facilitators providing additional feedback regarding aspects of the patient's responses that could have been better followed up and aspects that warranted empathic acknowledgment and possible referral for counseling.During the didactic session, residents were invited, using open-ended prompts, to openly share comments and reflections about providing care for patients with histories of trauma. Residents were also invited to discuss what could be improved in their residency training to help them feel better prepared and more effective at talking with their patients about trauma and managing traumatic stress. Responses were intended to demonstrate informal feedback based on residents’ experience of the didactic module. A facilitator recorded verbal statements that residents made during the session and immediately following the session one-on-one with a facilitator. Comments and reflections from residents who sent emails later, after the session, were also saved for this purpose. These comments and reflections were compiled by the faculty leader to serve as feedback on the module.16 The assessment tool was distributed to residents via email link to an electronic survey utilizing the REDCap platform. A copy of the assessment tool is provided in Following the didactic and role-play module, residents had the opportunity to complete an anonymous assessment of their beliefs, level of awareness, and sense of efficacy related to the delivery of trauma-informed care. The purpose of this assessment tool was to gather information about residents’ level of awareness and sense of efficacy in treating pregnant patients with histories of trauma. Items on the assessment tool were slightly adapted from an existing research measure designed to assess trauma providers’ awareness, views, and practice of trauma-informed medical and nursing care.17Data collected from this assessment of OB/GYN residents and presented here are intended to guide future adaptations of this trauma-informed OB/GYN didactic focused on assessing and addressing trauma histories in pregnant patients. Responses collected from residents who participated in this module have also been included in a larger research study of medical providers’ personality traits and sense of efficacy in delivering trauma-informed care.Finally, during a session debrief following the didactic, comments from facilitators were collected about what went well and what could be improved for future sessions. Facilitators also commented on direct observations made during the role-play, given that the faculty leader and all facilitators were able to observe only their own small groups during the role-play.The Rush University Medical Center Institutional Review Board granted ethical approval for the research procedures described in this report under exempt status.18 we conceptualized the evaluation of the impact of our module in terms of residents’ reactions to participating in the module and in the learning that they demonstrated following the module. The role-play exercise offered the most robust opportunity in terms of observing and gauging residents’ comfort with the learning materials, using terminology in the communication template, and responding to the patient's answers provided in the trauma narrative. Navigating the how-to process of asking about trauma, what to say, and what not to say appeared to be the most challenging for residents; hence, facilitators felt that role-play was probably the most useful learning strategy.According to Kirkpatrick's pyramid,Facilitators observed the role-play and provided feedback regarding aspects of the patient's responses that might warrant follow-up questioning or empathic acknowledgment. For example, when the patient reported pain with sex and said she “goes somewhere else in her head,” facilitators reinforced that this might signal a need for following up on pain and associated symptoms, as well as for reflecting the patient's response with empathy, by saying, for example, “It sounds like there are some difficulties/issues you are having with sex with your boyfriend that you try to distract yourself from. It sounds like that might be hard/unpleasant for you. Would you like to tell me more about that? There might be something we can try to do to help with the pain.” Facilitators also offered feedback on potential opportunities to provide information or referrals for counseling, again using empathic reflection to approach the topic. For instance, when the patient said she was “fine” and did not need mental health treatment but acknowledged that past abuse meant that she avoided certain family members, a possible response could have been “It can be difficult when you feel like you have to change your actions because of something someone else did. It affects your life,” or “Experiences with abuse can affect people's lives in different ways. Sometimes counseling can help with issues like family/partner relationships. Let me know if you would ever like more information, we can always talk more about it.” Facilitators emphasized that the goal in the moment was not necessarily to guide the thread of conversation to fully examining and solving a problem that might be related to past trauma. Rather, the goal was to open the door to further dialogue by asking a few open-ended questions and responding empathically, thereby increasing the likelihood that the patient would feel safe to share physical, social, and emotional trauma-related problems to the extent that they were affecting her current functioning. These issues could be set aside to address at a later time; however, facilitators emphasized that patients were more likely to feel comfortable engaging in such a conversation when the initial assessment and response were clear, nonjudgmental, and empathic.Additionally, we assessed residents’ sense of efficacy in delivering trauma-informed care to their pregnant patients in obstetrics settings. Although skill competence was not itself a specific learning objective of this module , perceived sense of efficacy ratings were deemed informative in guiding future development of trauma-informed training for OB/GYN residents. We further summarize the findings from our learning assessment and qualitative feedback (reactions) below. We also summarize reactions of the facilitators in conducting this module with OB/GYN residents.•○“I was really worried about having to [listen to] all the graphic details of the patient's trauma. But once you use the skills you realize that's not what this is about.” [senior resident]○“I had a patient who was sexually assaulted. I just used one of the phrases on this worksheet and I saw how she immediately relaxed.” [senior resident]○“We are the ones who do the pelvic exams. If the patient is anxious or upset, it's our job to help them or we could make things worse.” [junior resident]○“You can just tell the patient that if they have any of these things [past traumas] it affects their health. That way you show you aren't prying.” [senior resident to junior resident]Comments during didactic portion:•○“I feel like I don't know what to say to these patients. I really need help with this.” [junior resident]Comment during role-play exercise:•○“It definitely brought me to reflect on some ‘stuff’ that I face on a day-to-day basis. [Separating work and personal life] is nearly impossible when I am treating a patient affected by past illness/trauma. What resources can I look up for myself and my co-residents to help cope with these feelings?” [junior resident]Email communication following didactic:Comments and reflections from residents recorded during or immediately after the module or later in writing to the faculty leader revealed a number of important findings. Residents reported that this topic was highly relevant to their clinical practice given the number of patients they treated who were affected by trauma. While remarking that these skills did not fully address their concern for managing a patient with current or ongoing trauma, residents acknowledged that they could be applied to a variety of clinical situations in which a patient struggled with traumatic stress and needed additional support. Via email, one learner wrote that addressing how treating patients with trauma could personally affect residents sparked an interest in seeking support for preventing the learner's own secondary traumatic stress/vicarious trauma. The lead faculty member responded to this email, validating the learner's experience and applauding their awareness of these emotional responses, as well as inviting them to use staff psychologists as a confidential resource for additional tools and support. The faculty leader did not probe for more specific details from the learner but normalized their feelings and the importance of bringing challenging experiences to trusted mentors, peers, and other institutional support services. Specific comments/reflections from residents are listed below:16 The proportion of residents providing correct answers to these questions was variable, as shown in the A total of 14 OB/GYN residents (67% response rate) completed the assessment tool on beliefs, awareness, and sense of efficacy in delivering trauma-informed care. Results of the responses to the assessment tool are presented in the •○“The residents seemed to really hunger for information and the specific ‘how-to’ as well as the opportunity for practice and to get expert feedback.”○“Having senior residents model communication for junior residents was useful because they often had good case examples of when skills were used effectively, but occasionally senior residents did not provide the most effective or helpful modeling and may still need to be corrected/shaped.”○“There was some defensiveness observed on the part of some residents who resisted engaging in the roleplay and use of direct/explicit trauma language.”Observations:•○“Most useful was actual demonstration and engaging them in practice.”○“Spend more time on demonstration of communication skills, practice, and providing feedback.”○“Medical providers seem to really benefit from/need practical tools such as the laminated cards with critical steps as a reminder.”Most useful: emphasize role-play/practice/concrete tools:•○“If time is limited, reviewing diagnostic criteria for PTSD is not necessary.”○“Spend less time on lecture/didactics or keep very simple and concrete.”Less useful: lecture/didactic/extensive background:Facilitators commented that this module addressed an important topic that most residents felt they were insufficiently trained to address effectively. Facilitators observed some defensiveness on the part of a few residents upon receiving feedback or being instructed to ask about trauma histories directly. However, they noted that most residents were extremely grateful to have resources describing concrete steps toward eliciting sensitive information that could affect a patient's health and specific examples of how to respond when a patient endorsed having a history of past traumatic events. Observations and suggestions for improvement from facilitators included the following:6 Moreover, curricula specifically designed to address the learning needs of obstetric residents were found lacking in the literature. The module was introduced into the OB/GYN residency curriculum in academic year 2016-2017. At the end of the module, learners were expected to (1) identify symptoms of traumatic stress and the potential impact of traumatic stress on pregnancy outcomes, (2) identify common barriers to effectively addressing traumatic stress in obstetrics settings, and (3) utilize empirically supported approaches to assess a patient's trauma history and respond to disclosures. These objectives were achieved through a 2-hour combined didactic lecture and skills demonstration and practice delivered by experienced educators.The purpose of this module was to give obstetric residents the knowledge, framework, concrete steps, and safe environment to practice assessing histories of trauma in pregnant patients. The rationale for developing this module was twofold: Trauma history is considered a risk factor for adverse outcomes of pregnancy, and ACOG recommends screening and appropriate response to histories of abuse, violence, and trauma among patients who are pregnant.Overall, the module was successful in meeting students’ needs and our proposed objectives. The 2-hour didactic was well organized and well received. The allotted time was deemed sufficient to provide a basic overview of traumatic stress and its manifestations in pregnancy, concrete guidance on how to conduct an empirically supported assessment of trauma history, and a chance to conduct skills practice with residents and their peers. We believe this module provides a clear, organized, and effective learning experience with an appropriate level of content and opportunity for practice for obstetric residents.In reviewing the results of our assessments and feedback from both facilitators and learners, we identified four limitations, which offer opportunities for future improvement or expansion of the module in its current form. First, our assessment of awareness and sense of efficacy in delivering trauma-informed care highlighted potential areas for future focus. Residents demonstrated awareness gaps in understanding the likelihood of developing PTSD following trauma, which could be associated with overpathologizing or underpathologizing patients who are survivors of trauma. Residents also reported lower sense of efficacy involving counseling patients about traumatic stress symptoms and treatment and helping patients identify specific coping strategies to minimize trauma triggers in the obstetric environment. It may be useful to expand the content of the module either through in-session learning or premodule readings and materials on the topic of traumatic stress. Although the focus of this module was assessment of trauma history and responding to disclosures, residents may feel more confident performing this task if they have a more-solid understanding of the effects of trauma and psychopathological responses to trauma. Helping patients to identify specific coping strategies to deal with active trauma symptoms in the context of obstetric care was also not the focus of this module; however, it is undoubtedly important. A future iteration of the module could include addressing trauma symptoms and managing triggers, for example, during invasive exams and procedures or in preparation for potentially retraumatizing experiences such as childbirth, obstetrical surgeries, and obstetrical emergencies.Second, it was observed that having senior residents practicing alongside junior residents was helpful in some, but not all, cases. Senior residents have more experience to draw from, but this did not always lead to effective modeling for junior residents. It may present a challenge to teach to different levels of training in one 2-hour didactic session. One possible opportunity for improvement could be to deliver the module to smaller groups of residents based on their training year, tailoring practice according to the groups’ varying levels of clinical experience.Two additional limitations concern the assessment methods used to evaluate the module. Although we present information regarding learner feedback and reflections, formal qualitative assessment methods such as focus groups, structured interviews, or evaluation forms were not used. Comments from participants may have been biased in that they may have come only from participants with favorable views of the module or of the necessity for trauma-informed care. A final limitation concerns the lack of tests of the effectiveness of the module. The assessment tool was distributed only after the module and therefore does not reflect pre-post change in any of the topics assessed. Additionally, due to time constraints, the module did not involve an opportunity to formally test knowledge and skills in a formal standardized patient encounter. Moreover, assessment of residents’ sense of efficacy cannot be assumed to be a reliable measure of actual competence. It is unknown how the information and practice residents received translated into practice outside the classroom setting. It would be useful to determine the effectiveness of the module using the included standardized patient case in a formal simulation setting where learners have the opportunity to practice and receive feedback from standardized patients as well as feedback from peers and program instructors.Notwithstanding these limitations, our results demonstrate that this education activity can fill an important gap in OB/GYN resident communication skills learning, providing knowledge, tools, and a safe environment in which to practice asking patients about a highly sensitive topic (trauma history). The reactions of some participants suggest that they have begun to reflect on and apply the skills. One response from a resident also prompted us to include a specific acknowledgment of how discussing trauma can raise issues related to the learners’ own trauma/secondary trauma, and future use should include an acknowledgment of this along with relevant referral resources. Although designed and examined in obstetric residents who had already acquired clinical training and experience with medical patients, the module and its contents are sufficiently introductory to be suitable for students/trainees in other programs, such as general medicine, nursing, midwifery, and physician's assistant programs. Given the prevalence of traumatic stress and the associated risks of adverse medical outcomes across various medical populations and settings, we believe that modules such as ours could be integrated into trauma-informed care initiatives at the organization level. These materials can be seen as a step toward creating trauma-informed systems where members at all levels of the health care organization (not just clinicians) are equipped to identify traumatic stress and respond effectively.Didactic Facilitator Guide.docxPowerPoint Slides.pptxHandout 1 Sample Chart of Pregnant Patient With PTSD.docxHandout 2 Communication Template.docxHandout 3 Sample Trauma-Informed Practice.docxHandout 4 Sample Trauma Narrative for Role-Play.docxPocket Guide for Trauma History Screening.pdfAssessment Tool.docxAll appendices are peer reviewed as integral parts of the Original Publication.


To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics.Experts in ‘interval imaging’ (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed.Meningioma and glioma were identified as priorities for interval imaging utility analysis. The “monitoring biomarkers” most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value.Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management. Over the last decade the treatment landscape for adult brain tumours has changed incrementally for some tumour types, such as metastases, where there have been improvements in systemic therapy and brain radiotherapy . For oth“Interval imaging” was first introduced into neuro-oncology in 1977 by Victor Levin, shortly after the introduction of computed tomography (CT) . These eDeriving an evidence base surrounding current imaging practices is important for several reasons. There is a lack of biological specificity for contrast enhancement, particularly in the context of treatment effects and pseudophenomena, which can confound imaging assessment. There is also variability in clinical adoption of interval imaging practice across UK and European neuro-oncology centres which is unlikely to be in the best interests of patients or healthcare systems , 17. It The purpose of this position statement is to summarise the current evidence base for the utility of interval imaging in brain tumours and to propose potential studies for future evidence gathering incorporating the disciplines of data science and health economics.Box 1The National Institute for Health Research (NIHR) James Lind Alliance (JLA) brings patients, carers and clinicians together in Priority Setting Partnerships stating that “addressing uncertainties about the effects of a treatment should become accepted as a routine part of clinical practice” and that “patients, carers and clinicians should work together to agree which, among those uncertainties, matter most and deserve priority attention”.In 2015, the group met to establish the ten highest clinical priority uncertainties in neuro-oncology in the UK. Number two is: “what is the effect on prognosis of interval scanning to detect tumour recurrence compared with scanning on symptomatic recurrence in people with a brain tumour?” Patients expect imaging will give an accurate account of the effect of treatment and either reassure or initiate a change in the treatment plan. If there is uncertainty regarding progression, that leads to anxiety until the next scan or specialist MR imaging. In addition, if there is minor imaging progression only, there may be the clinical dilemma as to whether to change management if there are further options, even though the patient has had no clinical deterioration and it is not known whether earlier pre-symptomatic intervention improves survival.This might be interpreted as:“For me, a patient, does earlier scanning to detect asymptomatic progression improve my quality of life and survival, or does it not make any difference, or make it worse?”And:“Would I, as a doctor, improve the quality of life and survival of my patients if I monitored them more proactively and detected progression before it became symptomatic or does it not make any difference or make it worse?”Clinicians, scientists, and patient advocates and representatives with expertise in interval imaging, data science, health economics or trial management of adult brain tumours, convened in London, UK, in April 2019 in conjunction with a National Cancer Research Institute (NCRI) Brain Tumour group workshop. Available evidence for interval imaging pathways for different tumour types was discussed in the context of research recommendations of previous publications, including the UK’s National Institute for Health and Care Excellence (NICE) brain tumour guidelines NG99 , 5, 16. Following explicit agreement that there was an evidence gap, and that the JLA priority , meningiNeuro-oncology multi-disciplinary team meetings  consider longitudinal patient management, with serial imaging follow-up having a central role. Meningioma and glioma imaging follow up schedules from UK’s National Institute for Health and Care Excellence (NICE) brain tumour guidelines NG99 are shown in The emergence of novel therapies, such as immunotherapy have created challenges for follow-up imaging of glioma in clinical trials, with pseudophenomena occurring in up to 5% of patients leading to the development of modified response assessment approaches such as iRANO . The cenAlthough MRI is a safe and effective technique, structural imaging can lead to false positive, false negative, and indeterminate results, particularly relating to post-treatment related pseudophenomena in glioma. In glioblastoma, pseudoprogression is an early post-treatment related effect typically occurring within 6 month of finishing concomitant temozolomide and radiotherapy whereas pseudoresponse typically occurs after anti-angiogenic agents such as bevacuzimab have been administered. False positive progression and false negative treatment response are manifest as an increase or decrease in MRI contrast enhancing volume respectively. Confounding of treatment response commonly occurs with the use of current standard interval imaging conventions in therapeutic and novel imaging glioma trials due to the impact of such pseudophenomena . DelayedPatients undergoing MRI often experience anxiety prior to and during scanning . Up to 3Uncertainty is defined as an individual’s “lack of ability to determine the meaning of illness‐related events” . In patiThere are several sources of low-level evidence (level 4) indicating that patient and carer anxiety related to perceived unnecessary MRI scans or inaccurate or indeterminate imaging findings in primary brain tumours is a concern. This was a motivating factor behind the James Lind Alliance Priority Setting Partnership priority to establish the value and benefit of neuro-oncological interval scanning . Study dThere is no robust evidence (< level 3) to support the value or lack of value for the imaging practices currently used to monitor disease or to determine the response of any treatment given in adult brain tumours . There iAn understanding of current practice is critical to subsequent study design. A recent UK-wide national clinical practice survey on the use of interval imaging in glioblastoma management (GIN CUP study) showed considerable variation between centres . SimilarIn summary, there is considerable variation in interval imaging practice between centres during the glioblastoma post treatment follow-up period which should be considered in the study design of interval imaging value. Neuroimaging is believed to be crucial in making subsequent plausible management decisions once treatment is initiated, however there is a paucity of evidence for this assertion at all timepoints. Additional evidence, therefore, needs to be obtained to determine whether imaging protocols used in current routine clinical practice, and the type of neuroimaging performed at each component of the pathway, result in a measurable and impactful change in management (as opposed to the perception of a change or impact). Determining whether there is a change in outcome and value  is key.Economic evaluation addresses issues of efficiency and cost effectiveness: are the resources required to provide the intervention, in this case MRI scans, justified by the health benefits? If the MRI scan offers no health benefit, then the intervention is not considered cost effective, with robust economic evaluation required to determine under which circumstances cost-effectiveness is achieved. Whilst retrospective analyses may determine to some extent whether there has been a change in management, prospective studies are needed to quantify the benefit in the context of confounds.To determine cost effectiveness, an estimate of the impact of imaging on overall resource use is required as well as an estimate of the impact of imaging on survival and quality of life. Consideration of resource data collection is important in the design of future studies. Prospective collection of quality of life data can support a within-trial analysis of quality adjusted life-years . To inform QALYs, quality of life is typically measured using generic quality of life instruments, of which the most commonly used are the EuroQol EQ-5D , the SF-Trial follow-up is frequently insufficient to capture the full implications of monitoring and treatment on patient costs and outcomes. A decision model is commonly used to extrapolate costs and outcomes beyond trial follow-up, often over the remaining lifetime of the patient cohort. The most commonly used is the Markov model, which captures patient trajectories as a sequence of health states representing progression of the disease . EstimatDeriving evidence to determine the cost effectiveness of interval imaging requires consideration of the impact of imaging on downstream costs and outcomes. Downstream costs for surgical treatments such as craniotomy or licensed chemotherapy drugs can greatly outweigh the costs of the imaging. Hence quantifying small changes in treatments arising from imaging is important. Therefore, any design or modelling to optimise interval imaging cost effectiveness in routine clinical practice should incorporate changes in the costs of any subsequent alteration in treatment i.e. related and opportunity costs. For example, the model should incorporate changes in the costs of continuing expensive and ineffective therapies which themselves may be associated with adverse effects; changes to surgical procedures which themselves may be associated with reduced or prolonged hospital stays; and changes to the costs of rehabilitation if the clinical impacts of progression of underlying disease are altered.The conclusions of any health economic design framework described above are most applicable to integrated healthcare systems such as the UK. In these healthcare systems, imaging was historically considered relatively costly, and most agencies endorse rationing which can limit use. However, other reimbursement models in other healthcare systems can incentivise additional investigation, as reflected by the wide discrepancy in MRI use between countries .Beyond providers, there are individual financial implications for imaging. For example, 54% of carers of US patients with high-grade gliomas out of active treatment had costs of $271 per month with transportation to hospitals amongst the greatest out of pocket costs . These pMore evidence to determine the cost effectiveness of interval imaging incorporating the patient, carer, and healthcare system is required. Careful study design using standard tools should achieve this. Evidence on cost-effectiveness will improve care pathways in all systems, and is central to the efficient use of resources in centrally funded healthcare systems.In silico studies are those performed on a computer or via computer simulation. Sophisticated algorithms or simulations can advance scientific understanding, although the inferences drawn must recognise the limitations introduced by the simplified or reductive framework. The results of these simulations can be tested in existing trials or serve as a guide for future trials. Machine learning applications may move beyond inferential statistical approaches to attempt to extract more accurate predictions from complex datasets. Such approaches for imaging monitoring biomarkers in neuro-oncology are at an early stage of development in terms of clinical validation and applied techniques are not yet ready to be incorporated into the clinic  the clinical context may not be represented with a decreased ability to perform holistic evaluations of patients, with loss of valuable and irreducible aspects of the human experience such as psychological, relational, social, and organizational issues  accl issues  althoughl issues ; (3) binl issues  which mil issues ; (4) ovel issues . FurtherNonetheless, we emphasise that machine learning models have key advantages: whilst three decades ago it was noted that they require less formal statistical training given developments in software , 74, morAdvances in brain tumour database curation will facilitate integration of imaging data with demographic, clinical, and molecular marker data into large databases .This Interval Imaging Incubator Day meeting was facilitated and funded by TB, speaker’s bureau for AbbVie and Siemens Healthineers. Craig Buckley, Head of Research and Innovation – Siemens Healthineers GB&I. JC, BrainMiner Founder. Involved in machine learning enterprise and business. JK, involved in enterprise and business. MM, BrainMiner Founder. Involved in machine learning enterprise and business. SO, BrainMiner Founder. Involved in machine learning enterprise and business. MP, received payment for consultancy work from Merck not related to cancer. AW, unrestricted educational grant, Bayer Schering, consultancy work and honoraria not related to cancer.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute idiopathic maculopathy (AIM) is a condition reported to occur in young adults, which is classically characterized by the development of a unilateral serous macular detachment that commonly follows a flu-like illness. A 27-year-old female patient complained of diminution of vision in her left eye, of acute onset and progressive course for 2 weeks. She had a history of a flu-like condition 2 weeks prior. Following clinical examination, multimodal imaging analysis, and laboratory investigations, she was diagnosed with unilateral AIM, associated with atypical findings that were not previously reported to occur with AIM, including cystoid macular edema, flame shaped retinal hemorrhages, extensive hard exudates, and juxta-foveal yellowish intraretinal lesions. This may have been due to the more severe inflammation and concomitant phlebitis that was associated with this case compared to previously reported AIM cases. It is suspected to follow infection by Coxsackievirus in some reported cases [2].Acute idiopathic maculopathy is a condition reported to occur in young adults and is classically characterized by the development of a unilateral serous macular detachment that commonly follows a flu-like illness [1].The condition was initially described as a unilateral neurosensory detachment associated with thickening of the underlying layer of retinal pigment epithelium, with vitreous cells and intraretinal hemorrhages occurring in some patients. However, these manifestations usually spontaneously disappear with no recurrence. Fluorescein angiography typically shows early hypofluorescent and hyperfluorescent areas with late increase in hyperfluorescence and associated dye pooling . Later, new features associated with acute idiopathic maculopathy were reported, including papillitis with prominent veins and mild phlebitis, eccentricity of lesions, the association with pregnancy, peculiar subretinal exudation, and bilateral affection , characterized by cystoid edema of the macula, subretinal fluid, flame-shaped hemorrhages, and subretinal exudation. This may have been due to a more severe inflammation caused by a different organism or an exaggerated host immune response.This case represented a relatively more severe form of acute idiopathic maculopathy than previously reported cases . The associated phlebitis may have resulted in a picture similar to an occlusion of a retinal vein branch characterized by flame shaped hemorrhages in the retina with more severe leakage leading to the cystoid edema of the macula and subretinal exudation. The peculiar intraretinal material that was present nasally and temporally to the fovea was thought to represent the accumulation of inflammatory cells or debris as previously reported [3]. This material has also been previously reported to present as a pseudohypopyon or vitelliform material, which supports an inflammatory etiology for the condition .The presence of more severe manifestations in the reported case may have been due to the occurrence of more severe phlebitis than has previously been reported in other cases of acute idiopathic maculopathy [7].In conclusion, a unilateral acute idiopathic maculopathy case associated with more severe features than previously reported, including cystoid edema of the macula, flame shaped hemorrhages in the retina, and subretinal exudation, was reported. Depicting the unusual and rare features associated with a condition is necessary to help avoid misdiagnosis and unnecessary treatment as has been previously reported in cases of acute idiopathic maculopathy [Consent for publicationThe patient signed a consent form for publication of her images.Conflict of interestsThe author declared that she has no competing interests.FundingNo sources of funding were available.CARE guidelinesThis study adheres to CARE guidelines for reporting case reports.AcknowledgementsNone.Ethical approvalThis report was approved by Cairo University research ethics committee and followed the tenets of the Declaration of Helsinki.