Stroke as the most frequent cause of disability is a challenge for the healthcare system as well as an important socio-economic issue. Therefore, there are currently a lot of studies dedicated to stroke recovery. Stroke recovery processes include angiogenesis and neuroplasticity and advances in neuroimaging techniques may provide indirect description of this action and become quantifiable indicators of these processes as well as responses to the therapeutical interventions. This means that neuroimaging and neurophysiological methods can be used as biomarkers—to make a prognosis of the course of stroke recovery and define patients with great potential of improvement after treatment. This approach is most likely to lead to novel rehabilitation strategies based on categorizing individuals for personalized treatment. In this review article, we introduce neuroimaging techniques dedicated to stroke recovery analysis with reference to angiogenesis and neuroplasticity processes. The most beneficial for personalized rehabilitation are multimodal panels of stroke recovery biomarkers, including neuroimaging and neurophysiological, genetic-molecular and clinical scales. Stroke is an acute cerebral, spinal, or retinal vascular accident with neurological dysfunction that persists longer than 24 h, or one of any duration when infarction or hemorrhage corresponding to symptoms is demonstrated by imaging (computed tomography/ magnetic resonance scans) or autopsy . The cliFor outcome prognosis, recovery processes such as angiogenesis and neuroplasticity should be analyzed. Angiogenesis is a renewed growth of blood vessels to restore blood supply to the damaged brain tissue and it occurs after stroke ,18. ThisNeuroimaging is usually associated with differentiating ischemic from hemorrhage stroke in the acute phase; it also has a crucial role in ischemic stroke patients’ selection for novel treatment options, including late window thrombectomy. In this review, we emphasized the role and potential of neuroimaging techniques for post-stroke recovery prediction. Correlating recovery prediction with measurements entitles researchers to use determination of biomarkers. The FDA-NIH biomarker working group presented the following definition of biomarker: “A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention” , consideAngiogenesis after stroke is a complex and multistep process, involving (after gene transcription and releasing proangiogenic factors) endothelial cell proliferation, vascular sprouting, and finally microvessel formation . In the In many current studies, neuroimaging techniques are employed to assess and understand post-stroke impairment. Understanding neural mechanisms of brain tissue damage as well as regeneration processes could be essential for predicting recovery and monitoring therapy. Such neural mechanisms of recovery involve in particular the perilesional tissue in the injured hemisphere, but also the contralateral hemisphere, subcortical and spinal regions . All thoMRI is an essential clinical tool for diagnosing stroke severity, implementing treatment and predicting outcome . MultimoMRI also delivers a method for assessing indices of white matter integrity and remodeling following ischemic stroke through diffusion-based methods. Measures of corticospinal tract (CST) white matter integrity is possible by diffusion tensor imaging (DTI) that uses anisotropic diffusion to estimate the axonal (white matter) organization of the brain. Ratio and asymmetry index of fractional anisotropy (FA) between ipsi- and contralesional corticospinal tracts (CSTs) is a very popular predictor in DTI studies. In general, a lower FA value of the ipsilesional CST may indicate greater damage tp the CST that can lead to more Wallerian degeneration of CST axons . It has After stroke damage, we can observe a dynamic process of changing brain activation patterns. Measurement of brain function presents complexities that do not increase with the measurement of anatomy. The way to follow this complexity is functional MRI (fMRI), which measures brain activity by detecting changes associated with blood flow. It is considered that neuronal activation and cerebral blood flows are coupled . The mosThe next technique that allows assessment of the function of brain tissue is MRS (magnetic resonance spectroscopy). The presence and concentration of various metabolites is analyzed based on the principle that the distribution of electrons within an atom cause nuclei in different molecules to experience a slightly different magnetic field. In a study by Blicher et al., the higher GABA level in ipsilesional M1 was related to better motor function improvements after constraint-induced therapy . In a reElectroencephalography (EEG) is the most common, non-invasive method to record spontaneous or evoked electrical oscillation at various frequencies of the brain and, importantly, is one of the few mobile techniques available, unlike CT and MRI. Assessment of neuronal oscillations with electro or magneto-encephalography may supply an easy, available method to evaluate the balance between excitatory and inhibitory cortical actions . EEG sigThe aim of this article is not only to review neuroimaging stroke recovery biomarkers but also to analyze their application in treatment strategies. Therefore, it seems to be most beneficial to categorize individuals for personalized treatment based on multimodal panels including various biomarkers of stroke recovery. Recently introduced by Stinear et al., the Predict Recovery Potential (PREP) algorithm suggests combining clinical scales, transcranial magnetic stimulation, and diffusion-weighted magnetic resonance imaging to provide accurate predictions of upper limb function . This inFuture directions towards predicting post-stroke recovery and treatment outcomes could be machine-learning algorithms, which classify and predict the participants’ responsiveness to therapy . In thisThe use of neuroimaging techniques allows prediction of recovery potential more objectively, based not solely on functional clinical scales which represent a measure of impairment. However, it is relevant for stroke recovery to also consider other aspects, such as age, gender, type of stroke, type of treatment, as well as environmental factors. The importance of these factors should be assessed individually, but very often it is impossible to isolate one critical variable in clinical studies and therefore heterogenous groups might cancel individual benefits. To overcome this challenge, multimodal panels of biomarkers defining patients with greater recovery potential appear to be an appealing tool. Likewise, understanding the processes of angiogenesis and neuroplasticity that occur during stroke recovery, as well as monitoring these processes , is extremely important for planning effective treatment. Mentioned above, research using various types of biomarkers  is very promising for defining stroke rehabilitation protocol in future studies . To furt


Sarcomas are a diverse group of cancers of mesenchymal origin. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an uncommon and hardly reported neoplasm that is a malignant variant of the typically benign inflammatory myofibroblastic tumor (IMS). We discuss an exceedingly rare case of a 53-year-old patient with primary EIMS of the pericardium who presented in impending hemodynamic collapse. A transthoracic echocardiogram revealed a large circumferential pericardial effusion with tamponade physiology and an echogenic intrapericardial mass compressing the right ventricle to near obliteration. She underwent emergent sternotomy with resection and one cycle of chemotherapy with liposomal doxorubicin before having recurrent metastatic pericardial and pleural effusions, ultimately leading to her unfortunate passing. Sarcomas are a diverse group of cancers of mesenchymal origin that comprise approximately 11% of all cancers . SarcomaEIMS is distinguished by its morphological and histological elements, including a predominance of epithelioid cells with vesicular nuclei in a setting of myxoid stroma, inflammatory cell infiltrates, and the presence of spindle cells . In addiA 53-year-old woman with a past medical history of factor V Leiden mutation and multiple prior venous thromboembolisms with inferior vena cava filter placement presented with progressive fatigue and shortness of breath. On exam, she was in visible respiratory distress, hypoxic, and tachypneic. A computed tomography (CT) angiogram of the chest revealed bilateral pleural effusions and a large circumferential pericardial effusion Figure . A transOnly two months later, she was admitted to the medical intensive care unit for acute hypoxic respiratory failure requiring endotracheal intubation. CT of chest angiogram revealed multiple, large multi-loculated pleural effusions of the right hemithorax, causing complete opacification Figure . She undEIMS is a rare and recently defined entity that represents a more aggressive subtype of inflammatory myofibroblastic tumor (IMT). There have been several reports in recent years describing numerous cases of intra-abdominal EIMS, with a smaller number of cases being extra-abdominal, primarily in the thoracic or mediastinal spaces . The majThe diagnosis of EIMS can be difficult owing to its rarity and resemblance to other malignant diseases of mesenchymal or lymphoproliferative origins . In our Cardiac EIMS, specifically of pericardial origin, is exceedingly rare. The largest review of patients with cardiac IMT was of 57 patients performed by Eilers et al. . In theiClinician and pathologist familiarity with this disease can be crucial for diagnosis. It is important for clinicians to be aware of variations in the presentation of EIMS and for pathologists to be aware of the characteristic histological features as the course of the disease is often aggressive and rapidly fatal. In addition, proposed therapies that target specific markers typical of EIMS should consider variants that do not express the most common markers. Du et al. present one example of a proposed therapy that could target cases that express PD-L1 ; howeverEIMS is a rare and aggressive cancer that has conventionally been recognized by its intra-abdominal presence and distinctive histological and genetic characteristics. Our case demonstrates that pericardial manifestations and ALK-negative presentations are possible with EIMS. This sarcoma can be a challenge for both clinicians and pathologists to diagnose. Knowledge of more atypical presentations can aid in earlier diagnoses. In the future, targeted therapies should consider variants of EIMS that do not express the typical genetic markers as this may affect prognosis.


As germline genetic testing capacities have improved over the last two decades, increasingly more people are newly diagnosed with germline cancer susceptibility mutations. In the wake of this growth, there remain limitations in both testing strategies and translation of these results into morbidity- and mortality-reducing practices, with pediatric populations remaining especially vulnerable. To face the challenges evoked by an expanding diversity of germline cancer mutations, we can draw upon a model cancer-associated genetic condition for which we have developed a breadth of expertise in managing, Trisomy 21. We can additionally apply advances in other disciplines, such as oncofertility and pharmacogenomics, to enhance care delivery. Herein, we describe the history of germline mutation testing, epidemiology of known germline cancer mutations and their associations with childhood cancer, testing limitations, and future directions for research and clinical care. Approximately 10,470 children younger than 15 years old will be diagnosed with cancer in the United States in 2022  is held up as a model genetic condition for which the medical community broadly, and the field of oncology more specifically, has developed a wealth of experience in optimizing care delivery and cancer outcomes. Since 1959 , when TrGermline genetic testing strategies have improved from diagnoses historically based solely on clinical presentation and family pedigree studies to chromosome analyses using karyotypes, whole genome and/or exome sequencing, RNA sequencing, imprinting evaluations, and heterozygosity analyses. Critical to these advancements have been the determination of a reference or normal value for each amino acid sequence in the genome; however, the reference is limited by a narrow range of ancestral diversity from the initial small pool of participants who were involved in generating the normal ranges . Amino aEfforts to improve the diversity of the reference database and diseased populations alike are hampered by both historically decreased funding prioritization and distrust of the medical and scientific establishments among marginalized populations . The basThe prevalence and burden of germline cancer mutations in pediatrics is poorly understood. Childhood cancer etiology has historically been considered primarily idiopathic, with small percentages attributed to specific causes such as environmental exposure , viral triggers , or underlying genetic predisposition . While iThe Pediatric Cancer Genome Project (PCGP) began characterizing the prevalence of germline cancer mutations among children diagnosed with cancer who were enrolled across its clinical trials, resulting in a landmark paper published in 2015, which identified germline cancer mutations in 8.5% of cases using a cancer predisposition gene panel containing 60 genes . ImproveA further barrier to recognizing true cancer predisposition prevalence among those with childhood cancer lie in the study-specific selection of subjects. The majority of current analyses rely on samples collected for exploratory studies among patients included on clinical trials, most specifically those from Children's Oncology Group (COG) or from the National Cancer Institute (NCI) . This, bde novo mutations may underlie germline cancer susceptibility in a proportion of childhood cancer cases   Childhood Cancer Predisposition Workshop recommends germline testing for close to 50 specific pediatric cancer diagnoses, regardless of any other risk factor (ia (ALL) , germlinblastoma , 52, andin situ hybridization (FISH), immunohistochemistry (IHC), tumor sequencing, and tumor mutational burden being the most common modalities utilized clinically. The sensitivity of each of these tests at detecting genetic changes vary, with large chromosomal anomalies such as a trisomy effectively identified by karyotype while smaller mutations may require IHC or tumor sequencing for detection, and may also depends upon the specific test, with tumor sequencing more effective than IHC at detecting small sequence variations  inhibitors in the management of breast , prostate , and pancreatic cancer  for those with germline A fascinating therapeutic intersection between germline and somatic mutational profiling involves repurposing agents known to target somatic mutations for the oncology management of those with germline cancer predisposition. Such a basket trial that is specifically inclusive of those with germline cancer predisposition mutations is the American Society of Clinical Oncology-sponsored study: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (TAPUR) (NCT02693535). Similarly, we may not need to rely on as yet undeveloped therapies by moving targeted agents, such as immunotherapies, that are currently reserved for second- or later-line treatment to the upfront settings for those with germline cancer mutations.Borrowing from our Trisomy 21 model, in addition to identifying novel therapies or repurposing known agents in the treatment of cancers diagnosed among these populations, we may also improve outcomes by studying the effects of standard of care therapies. Aggregate data with short- and long-term follow-up would enable us to truly understand the burden of standard of care chemotherapy and radiotherapy on those with germline cancer predisposition. By understanding which specific agents have increased toxicity profiles for each germline cancer mutation and by developing supportive care interventions to mitigate that toxicity accordingly, such studies would provide insight into rationally modifying therapy with the tools we have already. For example, the recognition that methotrexate imparts greater toxicity  to thoseBRCA mutations  guidelines carry significant weight for insurance reimbursement, they are more focused on adult populations. Standardized insurance coverage for germline cancer predisposition testing would improve testing access, as it would allow financial gatekeepers to be more certain of anticipated reimbursement.The downstream impact of ambiguous reimbursement leads cancer predisposition testing to be deprioritized on health care resource utilization agendas. To best identify who to test, a thorough family history, including a pedigree analysis, is required,  yet thisThe siloization that occurs in the wake of reduced access to multidisciplinary care may lead children and adolescents with genetic cancer predisposition to be underserved. Depending on local practices, the medical home for a previvor may exist with a general pediatrician or a geneticist, neither of whom carry the expertise to manage an oncologic diagnosis, or a general oncologist, who may not have the depth of experience to diagnose and manage the full spectrum of potential cancers a previvor may develop. If the patient develops a cancer and their medical home moves to a subspecialized pediatric oncologist, that physician may not have the expertise to effectively tailor therapy based on the given germline mutation or to effectively navigate subsequent oncologic diagnoses that are outside their scope of expertise. A potential intervention to improve germline cancer predisposition literacy among practicing pediatricians, geneticists, and oncologists is through accrediting board-mandated Continuing Medical Education (CME) modules.At the intersection of testing limitations that lead to low diagnosis rates and lack of expertise in this subject field lies a marginalized population in an overwhelmed health care system. The strain on these supports is further exacerbated by the current SARS-CoV-2 2019 pandemic. Reports from the start of the pandemic anticipated an increased rate of cancer-associated death due to resource limitations leading to later stage oncology diagnoses . Post-paAutonomy and consent remain critical topics in pediatric germline cancer predisposition testing . AcquiriThere are ongoing efforts to optimize return of cancer predisposition testing results to pediatric cancer patients whose germline cancer mutation or VUS was suggested incidentally by somatic testing or identified on exploratory germline analyses. For example, St. Jude is conducting a study to analyze the psychosocial impact of return of germline results on the patient and family among children who already carry a cancer diagnosis (NCT04848142). Inherent across these studies and interactions, is respect for the patient's autonomy as perceptions of and decisions to receive a germline cancer predisposition diagnosis vary significantly across a cohort of people . CurrentThese considerations also extend to the management of children who have not been diagnosed with cancer but have a high risk of germline cancer predisposition, such as those with a confirmed pathogenic mutation in a first-degree relative. In these instances, the decision-making revolves around the risk-benefit ratio for germline cancer predisposition testing and takes into consideration the median age of first cancer onset associated with the given mutation. When the cancer onset tends to occur during the pediatric age range, then testing is considered worthwhile. This paradigm, however, does not consider if preventative opportunities implemented during the pediatric age range could decrease the likelihood of cancer onset in adulthood. Crucially, awareness of an increased cancer risk encourages a previvor to learn what is normal for their body and for all involved, physician and previvor/family alike, to diligently follow up any abnormal finding or persistent symptom; this can overall promote earlier detection of cancer and may improve survival outcomes.Additionally, awareness of a germline cancer mutation may provide impetus to follow recognized healthy lifestyles, such as maintaining a healthy weight, avoiding tobacco and heavy alcohol use, relocating to areas of decreased radon or nuclear/industrial waste exposure, and increasing uptake of anti-cancer vaccines such as the HPV vaccine. Beyond known cancer risk-reducing interventions that are broadly applicable, further studies can determine the true benefit of other potential interventions that are more targeted, such as early non-steroidal anti-inflammatory drug (NSAID) use to mitigate risk of developing colon cancer among those with hereditary gastrointestinal cancer predisposition , 110 or The intergenerational impact of a germline cancer predisposition mutations may also be felt even in the absence of a confirmed diagnosis. Current germline testing criteria have high points of entry and are based on a “sacrificial lamb” model, whereby sufficient numbers of first- and/or second-degree relatives must be affected by cancer to trigger evidence-based germline testing and insurance coverage . Furthermore, family history-based testing criteria presumes access to sufficient historical data, yet there is a high likelihood of limited family history due to small families, unknown family history, and/or death in the family from a competing non-oncologic cause . AdditioEven with a well-documented family history, germline cancer predisposition testing guidelines may be limiting. Various guidelines include those put forth by the American Society of Breast Surgeons (ASBS) for hereditary breast and ovarian cancer , revisedLiberalizing germline cancer predisposition testing criteria would enhance access to potentially life-changing results for both the patient and their family. The detection of a germline cancer mutation allows for cascade family testing and, through prophylactic procedures and interventions of newly diagnosed family, can save the lives of a proband's first and/or second-degree relatives and allow them to navigate life with their family present as opposed to their family members dying early of cancer . As testWhile strict germline testing criteria do help identify groups of people with a higher likelihood of having a positive result, there are systemic gaps that are more pronounced for pediatric patients, and gatekeeping the diagnostic test both enforces a sacrificial lamb approach that carries a heavy emotional burden on the remaining family and perpetuates marginalization of this population. On the opposite end of the spectrum, primary screening of the pediatric population, in the form of mass testing, is beyond the scope of this article, but has intriguingly been discussed in the context of newborn screening , 120. AcThere are many challenges and opportunities remaining to realize the potential of precision medicine among pediatric populations with germline cancer predisposition mutations. As the motivating example of therapy modification among children with Trisomy 21 diagnosed with AML has shown, dramatic improvements in cancer care and outcomes are possible. To reach this potential for all pediatric patients, more research is needed to (1) estimate the prevalence of germline predisposition among childhood cancer patients; (2) expand known associations between clinical and histological features and underlying germline cancer predisposition mutations; (3) determine the settings in which risk-adaptive therapy is appropriate, considering the high risk of second malignancies among patients with germline predisposition; and (4) expand the diversity of enrollment of children into therapeutic and research protocols to enable broader generalizability of research findings.SS and EM: article concept and design, critical revisions of the manuscript for important intellectual content. SS: drafting of the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the Children's Cancer Research Fund .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Virus neutralization data using post-vaccination sera are an important tool in informing vaccine use policy decisions, however, they often pose interpretive challenges. We systematically reviewed the pre-print and published literature for neutralization studies against Omicron using sera collected after both primary and booster vaccination. We found a high proportion of post-primary vaccination sera were not responding against Omicron but boosting increased both neutralizing activity and percent of responding sera. We recommend reporting percent of responders alongside neutralization data to portray vaccine neutralization ability more accurately. The World Health Organization (WHO) and the Coalition for Epidemic Preparedness Innovations (CEPI) among others use information on the neutralizing activity of post-vaccination sera as an early sign of vaccine performance against circulating VOCs. Since neutralization data could inform policy-making decisions regarding vaccine strategies, we reviewed the global evidence for current vaccines’ ability to neutralize Omicron, and stratified the results according to primary vaccination series and booster (both of which included homologous and heterologous regimes).Since its initial characterization in November 2021, the SARS-CoV-2 Omicron (B.1.1.529) variant of concern (VOC) has largely displaced the Delta variant in many parts of the worldNeutralization results were extracted from 50 studies meeting our inclusion criteria, providing data for 119 vaccine-specific observations based on 3150 sera  observations evaluated sera collected 0.5–1 month post-vaccination.Most primary series and booster observations were of mRNA vaccines  to 23.1-fold and 25.5-fold  and 13.4  and for inactivated vaccine classes  but varied within vector vaccine class  of included studies evaluated sera collected at peak immunity. We also demonstrate that relying only on fold decrease when the percent of responding sera is low can mask the true neutralizing activity of a vaccine, and, consequently, may lead to inaccurate inference of a vaccine’s ability to protect against infection and disease from variants, especially one as antigenically different as Omicron.The percent of responding sera is an overlooked but highly important parameter in assessing post-vaccination neutralizing activity against variants. The accuracy of fold decrease calculations can be misleading when the majority of sera show no measurable neutralizing activity against Omicron. This is because when serum measurements are below the limit of detection, the general practice is to assign them an arbitrary titer, which is usually either one log lower than the lowest dilution, or half the level of detection. This arbitrary value can have a large impact on the magnitude of the apparent fold change, since it can over- or underestimate neutralizing activity against a variant. It is thus important to also report the percent of responding sera to provide a more complete and accurate picture of a vaccine’s ability to elicit neutralizing immunity against variants.versus pseudoviruses. It is important to note, however, that although very low readings can be obtained when using pseudoviruses, the uncertainty connected to these readings increases proportionally the lower the reading is. This holds true for every reading obtained that is already below the lowest (starting) dilution used in the assay. Our suggestion to include the percent of responding sera in the results, helps to eliminate part of this uncertainty.The lower limit of detection varies greatly between assays that use live viruses Induction of high neutralizing titers against the homologous vaccine-seed strain is not only part of regulatory requirements, but also an important early measure of a vaccine’s success, since higher titers generally correspond to higher levels of protection, including against future circulating variants as antigenically different as Omicron. Our analysis shows that GMTs against the parent strain are lower after the primary vaccination series than after the booster dose and corresponded with lower percent of responding sera against Omicron after primary vaccination compared to post-booster dose.Although some vaccines and vaccine combinations appear to perform better than others, the wide heterogeneity in responses between studies observed for some homologous vaccines mean these data should be considered with caution. This is even more true for all heterologous vaccine combinations evaluated here, where data on their neutralizing ability were available from only 1–2 studies each, and therefore these results may not represent their true abilities. Nevertheless, such data are especially important in the current setting, where reliable clinical effectiveness data may not be available for all vaccines in use, and where administration of heterologous doses can be common because of supply or logistics issues. If meaningful appraisals of vaccine performance are to be made in order to inform timely policy-making decisions, there is an urgent need for more data on the vaccines currently in use. Using the WHO international standard (IS) and reporting results in international units (IU) could in theory allow for better comparison between assays. However, considering that the WHO IS has largely been depleted, and is found to have no neutralizing activity against Omicron variants, reporting the results in IU is not feasible.A possible limitation of our analysis may come from the inclusion of data from pre-printed articles, which should always be used with caution. Nevertheless, the use of these articles does not affect the main findings and recommendations of this manuscript, namely that neutralizing ability and % of responders against Omicron increase post-boost compared to primary vaccination series, and that there is a need for more data for certain vaccines and vaccine combinations. Both findings hold true regardless of the source of data (published or otherwise). Finally, using pre-prints in order to inform policy-making decisions regarding vaccine strategies has become acceptable during the pandemic, due to urgency of the situation and the need to respond and adjust policies as quickly and effectively as possible. Restricting the analysis to fully published literature would have resulted in the exclusion of relevant and useful data that could help inform our understanding of the impact of Omicron on vaccine performance.This work consists of analysis of data available in the public domain. No ethics approval is necessary.Studies containing neutralization data against the Omicron variant after primary series or booster vaccination were identified by searching PubMed and pre-print servers (bioRxiv and medRxiv) from November 1, 2021 until January 31 2022 using the following terms: “SARS-CoV-2” AND “Omicron” AND . Title and abstract were screened and those possibly containing relevant data underwent full text review. Relevant articles underwent data abstraction in real-time. Exclusion criteria included: sera collected after partial primary series vaccination; sera collected <7 days or ≥6 months post-vaccination; data collected without using a strain genetically/antigenically similar to the vaccine-seed strain as a comparison ; data from subjects infected with SARS-CoV-2 either before being vaccinated or after; data from cohorts that included immunocompromised individuals, or individuals with concurrent health conditions that are expected to affect vaccination-induced immunity (for example cancer patients). In addition, data from assays using pseudoviruses or virus-like particles were excluded if these viruses did not contain the full complement of mutations characteristic of the Omicron VOC spike protein. If any studies did not contain clear information on any of the exclusion criteria, they were not included in the analysis. Studies were screened by three reviewers working independently and collaborating when in doubt. A PRISMA diagram describing the literature search and study selection process is shown in Fig. 53, as well as in the Source Data file. Raw data can be found in the Source Data file. All neutralization data used were reported as NT50 titers. Median and interquartile ranges (IQR) of the fold decrease in neutralization activity, median percent responders, and median parent strain GMTs across all studies were calculated where possible (using the GMTs reported in each source reference) for each unique vaccine combination and plotted using GraphPad Prism 9 (version 9.3.1). Meta-analyses to estimate average effect size were not performed due to heterogeneity in the methodology of included studies.The fold change in neutralizing activity against Omicron (relative to the parent strain), the geometric mean titer (GMT) of the parent strain, and the percent of responding sera  were abstracted for each vaccine regimen. All references used to collect the source data can be found in the reference section of this manuscriptFurther information on research design is available in the Data Set 1REPORTING SUMMARY


Harnessing the effector mechanisms of the immune system to combat brain tumors with antigen specificity and memory has been in research and clinical testing for many years. Government grant mechanisms and non-profit organizations have supported many innovative projects and trials while biotech companies have invested in the development of needed tools, assays and novel clinical approaches. The National Brain Tumor Society and the Parker Institute for Cancer Immunotherapy partnered to host a workshop to share recent data, ideas and identify both hurdles and new opportunities for harnessing immunotherapy against pediatric and adult brain tumors. Adoptively transferred cell therapies have recently shown promising early clinical results. Local cell delivery to the brain, new antigen targets and innovative engineering approaches are poised for testing in a new generation of clinical trials. Although several such advances have been made, several obstacles remain for the successful application of immunotherapies for brain tumors, including the need for more representative animal models that can better foreshadow human trial outcomes. Tumor and tumor microenvironment biopsies with multiomic analysis are critical to understand mechanisms of response and patient stratification, yet brain tumors are especially challenging for such biopsy collection. These workshop proceedings and commentary shed light on the status of immunotherapy in pediatric and adult brain tumor patients, including current research as well as opportunities for improving future efforts to bring immunotherapy to the forefront in the management of brain tumors. The National Brain Tumor Society (NBTS) and the Parker Institute for Cancer Immunotherapy (PICI) convened a group of experts for focused discussions about advancing the impact of immuno-oncology (IO) in brain tumors Table . The worPrimary brain tumors, such as glioblastoma (GBM), have been remarkably resistant to immunotherapy, even though preclinical models suggest effectiveness. While immune checkpoint blockade molecules, notably targeting the PD-1 / PD-L1 pathways, have revolutionized treatment of other tumor types, brain tumors have shown limited efficacy in the adjuvant setting , althougBecause rational drug and clinical trial design in high-grade gliomas will be biomarker-driven, recent efforts have focused on generating relevant datasets for clinical and drug development decision-making. PICI has partnered with Cancer Research Institute (CRI) and American Cancer Gene Therapy (ACGT) non-profit organizations in a consortia effort to demystify heterogeneous expression of known immunogenic glial targets, and the quantity, quality and spatial characteristics of immune cells and immune-therapeutic targets across a large number of high-grade glioma samples, many of which are from patients involved in immunotherapy clinical trials. To generate a ground truth of biological signatures across the datasets, transcriptomic, genomic and protein data from assays that have provided unique insights into the biology and prognosis of gliomas –8 will bIn addition to facilitation a comprehensive evaluation of the immune microenvironment, partnership efforts between academia and non-profits have also focused on generating novel therapeutics. One area of intense intersest include chimeric antigen receptor (CAR) T cell therapies Table . To geneThis clinical experience shows that, for all three targets , locoregionally delivered CAR T cells, which are administered on weekly cycles in the outpatient setting without lymphodepletion, have been well-tolerated. Common adverse events include metronomic fevers, headaches, chills and fatigue that occur 24–72 h post each CAR T cell infusion. Concomitant with these toxicities are locoregional increases in inflammatory cytokines, including the IFNγ-responsive cytokines CXCL9 and CXCL10, along with an influx of endogenous immune cell populations detected in the CSF, suggesting that CAR T cell infusions alter the immune landscape. As is often observed with immunotherapies, patient antitumor responses have been mixed; although, encouragingly, many patients have experienced extended stable disease and/or long-term remission that is not typically achieved in the setting of recurrent GBM. One individual with multifocal recurrent GBM achieved complete tumor remission, even though the tumor did not homogenously express IL13Ra2 target antigen . Upon fuCAR T cell therapy is also being evaluated in pediatric brain tumors. For example, GD2, a well-recognized tumor target in several tumor types, is now being evaluated in brain tumors , 18. StaResearchers have not observed evidence for GD2 antigen loss and are examining samples obtained to understand the basis for resistance in an attempt to sustain and improve the anti-tumor effects. Everything currently understood about pediatric tumors thus far suggests that they have a lower mutational burden and are less immunogenic than the adult counterparts. In many correlative assays, including in the CSF, many inflammatory markers and impact of the myeloid cells are seen. Some lymphocytes are detected, but many are myeloid cells, which may be modulating the response perhaps in an adverse way.Although CAR T therapies demonstrated remarkable outcomes in treating hematologic malignancies, the above experience confirms that the development of effective CAR T therapies for solid cancers, including GBM, remains a challenge due to multiple barriers, including the antigenic heterogeneity, on-target off-tumor toxicities, and T cell exhaustion. For example, while a recent CAR study targeting epidermal growth factor receptor variant III (EGFRvIII) , safely https://www.proteinatlas.org), raising a concern of off-tumor toxicity outside of CNS. As a way to safely and effectively target GAAs, a novel synthetic Notch “synNotch” receptor system ) platform are (1) the retention of HSV ICP34.5 gene that endows viruses with full replication competency and enhanced potency in the face of host antiviral response, (2) a large transgene capacity enabling the tailoring of an optimal payload combination of up to 8 payloads to counteract the immune-suppressive drivers in GBM, and (3) a cell-specific attenuation strategy utilizing the tumor-to-normal cells’ differential expression of microRNAs. The first Oncorus product ONCR-177 for solid tumors with liver metastases is in an early-stage clinical trial (NCT04348916). The company is engineering a microRNA-attenuated armed oHSV drug candidate for GBM.Still, many hurdles need to be overcome before these approaches turn into successful immunotherapies for GBM. Participants of the workshop stressed the necessity for better mechanistic understanding of the effects of combinations with immune checkpoint blockade; the need for understanding how activation of cytotoxic T cells can generate meaningful clinical responses and prolong OS; the need for peripheral blood biomarker(s) of immune response that would be paired with tumor tissue; the need for better access to post-treatment tumor material from clinical responders; and implications of the high bar for responses in GBM set by response assessment in neuro-oncology (RANO) and immunotherapy response assessment in neuro-oncology (iRANO), which limit sample size for correlating clinical responses to immune activity.It is recognized that there are certainly limitations with preclinical models, however, such models still aid in understanding mechanisms of action and resistance, as well as testing basic cancer biology and immunobiology. Identification of biomarkers of interest should also be investigated, as they can provide a scientific basis or mechanistic rationale for particular combination approaches. This is crucial, as the mechanism of action plays a key role in selecting specific immunotherapies for combination approaches. Animal models are also critical to safety profile testing, and analysis of observed responses also factor into patient selection algorithms. Preclinical models can be useful for reverse translational studies in which unexpected responses (or lack of response) seen in the clinic can be traced to specific mutations in patients . PreclinSeveral challenges with preclinical models were identified during the course of the workshop, and there is a clear need to revisit expectations with preclinical models, which are the current bar for clinical setting evaluation. It is evident that we lack a true representative GBM model. Issues such as molecular drivers, relevant antigens, and the stroma in murine models may be significantly different from those in true GBMs. Furthermore, modeling of tumor heterogeneity can be challenging with preclinical models. This necessitates an increased investment in development and improvement of genetically engineered mouse models (GEMMs) or PDX models.. Lack of standardization with preclinical models is also a limitation . Future exploration of other animal models, including spontaneous glioblastoma in canines, is warranted .Organoid models for study of the tumor microenvironment may be used to supplement clinical and murine data. These models may be more representative of a patient’s tumor microenvironment, as they recapitulate some of the features of patient tumors. They are, however, limited in how long they can be kept viable ex vivo. Artificial intelligence (AI) and deep learning may also be used as a complement to preclinical testing to help validate hypotheses. In breast cancer, for example, there has been a recent emergence of models using AI and deep learning to help better predict outcomes. AI models can also be useful in helping identify biomarkers that are more prevalent than others.Performing multiomics analyses in a centralized or standardized approach on a subset of patients who had good responses to previous therapies or identified as potential candidates for response can yield important insights and generate novel hypotheses. In-depth analysis of patient subsets can help identify characteristics that lead to improved response. Additionally, selecting a subset of patients may help alleviate certain challenges  and expenses of doing such analyses on all the patients. A centralized approach can also help reduce the burden on labs that may lack the infrastructure to conduct such analyses, as well as provide reliable and consistent data.Although early clinical development can help identify a subset of patients who are good responders, inclusion of an unselected population in a phase 2 or 3 trial can potentially lead to dilution of clinical benefit. Thus, it may be of benefit to delay phase 2 or 3 trials to allow for identification of appropriate patients who are more likely to be responders. Enriching a final trial population with such patients can lead to improved outcomes with immunotherapies for brain tumors. This can further aid in advancing the treatment landscape and re-engage pharmaceutical and biotech companies (as there is a dampening of interest from negative outcomes). Creating infrastructure and platform trials that allow for collaboration toward a common goal  can also be of benefit.Although blood samples can provide important information, tissue biopsies and CSF sampling provide especially meaningful insights into the local microenvironment where therapies are delivered. Lumbar punctures allow for an increased sample volume (as compared with an Ommaya reservoir); however, serial lumbar punctures can be inconvenient and challenging for patients. On the other hand, the Ommaya reservoir for CSF sampling may be more feasible, well-tolerated, and allows for a time course over therapeutic treatment. However, challenges do exist with an Ommaya reservoir, including increased risk of infection, edema, and herniation.Earlier sampling of biospecimens  is ideal and provides an actionable baseline; however, appropriate timing for sampling also depends on the treatment modality and response of interest . Additionally, early sampling can be challenging for some patients who go directly into surgery. For such patients, a potential baseline may be the time point between surgery and before radiation is received. Challenges with sample collections on multicenter trials (ensuring consistency among centers) as well as outside of clinical trials  also exist. Data collection and subsequent analysis for identification of ideal timing of sampling is needed.As compared with other cancers, accessibility of brain tumors for tissue biopsies can be a major barrier. At certain institutions, resistance from clinicians on performing biopsies for patients randomized to the standard of care treatment arm can be challenging. Due to recent advances, tissue biopsy is now standard of care in pediatric DIPG, which may help overcome such challenges.Several advances in molecular testing have been made, yet certain challenges remain. Discordance between immunohistochemistry and molecular analysis for specific mutations can be a hindrance to decision-making. Limited mutation panels for testing at institutional pathology labs, especially community hospitals, can lead to exclusion of specific mutations, which may impact treatment choices. There is a need to inform patients about the potential to send out samples to Foundation Medicine or larger centers with broader panels for a more robust analysis. Lastly, the inability to analyze whole genome sequencing can limit further understanding of such datasets.Although coverage for isocitrate dehydrogenase mutation testing is a recent development, payers do not cover most molecular testing. The federal government may impact Centers for Medicare & Medicaid Services (CMS) coverage decisions; however, their influence on private health insurer decisions is limited. Potential avenues for overcoming barriers to coverage include conveying to payers the importance of testing for decision making  and targeting proprietary companies that private insurances may use to set medical necessity. Certain patient policy advocacy groups like National Brain Tumor Society are also working on legislation to improve coverage for molecular testing.Tumor heterogeneity is a major concern in GBM; however, approaches to overcoming these challenges do exist. In-depth genomics and immune profiling data from well-designed studies with small sample sizes can be of benefit. These data may help with patient response evaluation and identification of signals, which may indicate if specific immunotherapy is of benefit. However, such analyses may be challenging to conduct in trials with a large patient population.High-dimensional immune profiling can aid in understanding benefits of immune responses and in identifying tumor subtypes that may be responsive to therapies. Multiplexed ion beam imaging analysis of responder and non-responder tissues and targeting multiple TAAs or tumor-specific mutations, as compared to a single, widely expressed mutation/antigen, can also be valuable. Additionally, analyzing the impact of tumor genetics on the tumor microenvironment can aid in identifying drivers of suppression, which can help guide strategies for therapies with increased likelihood of overcoming suppression.Inter- and intra-patient heterogeneity necessitates the need for a personalized medicine approach. Identifying baseline tumoral characteristics  can help improve trial designs, drive optimal patient selection, and potentially identify resistance mechanisms. Additionally, preservation of tissue in a manner that is easy to share is also important for furthering consistent analyses between patients.The following strategies can be helpful in informing future trial designs: analysis of negative trials to better understand certain aspects that may have contributed to the outcomes ; avoidance of rushing into phase 2/3 trials and performing correlative analyses to better select populations for subsequent trial designs; and analysis of available data  from other solid tumor trials and leveraging those learnings for improved trial designs.Investment in workshops where investigators can discuss findings, followed by development of algorithms, as well as sharing of data as early as possible to help others make more informed decisions are areas of need. Additionally, a centralized platform that houses research from various investigators can help future researchers start from a more informed basis. It is important to note that hypotheses generated from retrospective analysis of samples  may be therapy specific. However, such platforms may allow for opportunities to examine overlap across similar therapies and identify potential signals of success or failure (which can be further tested).Improved outcomes observed with neoadjuvant anti-PD-1 immunotherapy, as compared with adjuvant therapy, in GBM  highlighThe following are also important considerations: neoadjuvant treatment may not be feasible for certain patients who may require emergency resection ; however, there may be an opportunity for neoadjuvant treatment in recurrent disease. Also, longitudinal analysis beyond clinical observations has been beneficial in moving the field forward. Innovative approaches for examining responses over time in patients, albeit small trials, can help identify certain trends and potential biomarkers. Finally, specific antigen − targeting therapies are necessary in GBM, as non-specific tumor approach may lead to autoimmunity against normal brain components.There is a need for better imaging techniques for response evaluation. Although objective response rate can be an ideal measure for treatment response over OS, limitations with imaging, especially differentiating between true progression and pseudoprogression, can be a challenge. At the National Institutes of Health (NIH), several resections for patients with negative outcomes to therapies have shown the presence of immune response without tumor or minimal tumor present (pseudoprogression). Misinterpretation of pseudoprogression as true progression can negatively impact outcomes, including discontinuation of effective therapy, a switch to another therapy (which may not be effective), and potential for compromising positive treatment results. On the other hand, misinterpretation of true progression as pseudoprogression can lead to continuation of ineffective therapy, leading to tumor growth and potential transition of care to hospice if eventually deemed untreatable. Furthermore, challenges with imaging may be contributing to the misconception that immunotherapy is not an effective GBM treatment. Unfortunately, serial biopsies are not considered practical for the evaluation of therapies for trials, as all patients may not be appropriate candidates for second resection or multiple resections. This fact further underscores the need for effective imaging and biomarkers that accurately reflect tumor activity vs. treatment effect or a combination of both.Matched cohorts from a registry or a synthetic control arm may be of assistance in defining responders vs. non-responders more effectively, as compared with change over time from baseline. However, challenges with permission to access and share such data given privacy regulations can be a hindrance. Patient-driven data gathering  may be a potential solution, although barriers to data for deceased patients may still persist.Challenges with criteria for RANO and iRANO as compared with Response Evaluation Criteria In Solid Tumors in stratifying clinical responders , as well as lack of criterion to help clinicians decide whether to continue treatment or not, also remain. Revising the criterion and investigating new magnetic resonance imaging sequences  or otherIt is a misconception that patients are not knowledgeable, given the advent of social media and online message boards, which allow patients to effectively share their knowledge and experience. Partnering with patients in treatment decision making (shared decision making), including review of evidence from preclinical models , and for clinical trial designs, including endpoints of interest, can be important from the patient’s perspective.Providing adequate information that is tailored to patients’ level of understanding and empowering them to make informed decisions is vital. Additionally, comprehensive information, including current and subsequent options , and therapy expectations  should be shared with patients. Quality of life measures, including emotional, social, physical, and cognitive functioning are valued by patients.Access to experimental drugs for N of 1 trials and omics analysis, inclusion of multiple brain tumor subtypes in clinical trials, and access to high-level summary of the proposed white paper for patients and caregivers are also meaningful to patients. Although patients do see the importance of clinical trials and research, interest in participation may vary depending on the stage of the patient’s journey.Several unmet needs exist in brain tumors, including exploring avenues to help bring IO to the newly diagnosed setting (current research and work is primarily in the recurrent disease setting); identification of putative markers or biomarkers that will help identify which patients are more (or less) likely to respond to immunotherapy ; access to therapy  for subgroups of patients who may derive benefit from them ; and research to help identify patient factors that render immunotherapy less effective in certain patients. In-depth profiling of biopsies may yield such insights. Another need is a unique data platform that allows for (a) integration of data from various models  and datasets, (b) retrospective analysis of data to help inform future trial designs, (c) functionality for input of data from various users (comprehensive datasets), and (d) development of an algorithm (AI learning) based on the available data to help guide decisions.Interaction between the CNS and the bone marrow in GBM is an understudied area. Better understanding of the life cycle of various myeloid cell compartment constituents from early progenitor cells to differentiation is needed . Identifying trends in myeloid cell skewing , as well as the effect of radiation and chemotherapy on the myeloid cell compartment also needs further research. Caution should be exercised when examining blood samples to understand the cell’s activity in the brain.Examining immunotherapy combinations  in smaller trials is necessary before implementation in larger platforms such as GBM AGILE . Caution


Women make up a growing proportion of the workforce and therefore many women experience menopause while in paid employment. We explored the prevalence of menopausal symptoms, the relationship between symptoms and coping with work and the risk factors associated with struggling at work during the menopause. The Health and Employment After Fifty (HEAF) community-based cohort of people aged 50–64 years was incepted 2013–2014 to study health and work. In 2019, female participants were asked to complete a questionnaire about their menopausal symptoms, and effect of those symptoms on their ability to cope at work. 409 women were eligible for inclusion. The commonest symptoms were vasomotor (91.7%); trouble sleeping (68.2%); psychological (63.6%) and urinary (49.1%). The prevalence of reporting symptoms was similar no matter which type of occupation women were performing at the time. Around one-third of women reported moderate/severe difficulties coping at work because of menopausal symptoms. Risk factors for difficulties coping at work included: financial deprivation, poorer self-rated health, depression, and adverse psychosocial occupational factors but not physical demands. More awareness is needed amongst employers in all sectors but women with financial difficulties and those with jobs in which they feel insecure, unappreciated, or dissatisfied are at greatest risk. In many countries, the participation of women in the work force has increased rapidly in one or two generations . In the Despite the potential impact of menopause on women’s working lives, this research area had received scant attention until the last decade. Since then, studies have shown that the self-reported work ability of women, as assessed using the Work Productivity Activity Impairment scale , is affeSome studies have explored the effects of different types of menopausal symptoms on work. For example, irritability and mood changes were found to have the worst impacts on job performance in one study of older female employees, although less so among women who were managers . AnotherWhilst these studies contribute useful information, they shed no light on whether menopausal symptoms affect women doing different types of work in the same or different ways. The few studies that have considered work characteristics have tended to focus only on one type of worker, namely teachers , nurses This was a cross-sectional analysis of data collected as part of the Health and Employment After Fifty (HEAF) study, the detailed methodology of which has been previously reported . BrieflyWomen who reported experiencing at least one of the menopausal symptoms while working were asked the following question “Do/did the menopausal symptoms cause you any problems coping with work?”. Possible answers were “no problems”, “minor problems”, “moderate problems”, and “severe problems”. Responses were combined in a binary variable so that those experiencing moderate or severe problems were compared with those experiencing minor or no problems.The baseline questionnaire included questions about: financial status , having anyone financially dependent (yes vs. no), qualification level , marital status (single/widowed/divorced vs. married/partnership), smoking (ex/never vs. current), alcohol consumption (low/moderate/heavy drinker), weekly leisure time physical activity (none/up to 5 h/between 5 and 10 h/more than 10 h), self-rated health (fair/poor vs. at least good), depression  , and weiTo reduce recall bias, analysis was restricted to women who either started the menopause within the previous 10 years or who reported that they were currently experiencing symptoms (irrespective of when the menopause started). Socio-demographic and lifestyle characteristics as well as characteristics of the job were described according to whether participants experienced moderate/severe problems coping at work or not. Frequency and percentage distributions, means and standard deviations were used depending on the nature of the variable. Due to the relatively high prevalence of the outcome, we used Poisson model with the option for robust standard errors to explore the associations between risk factors and problems coping with work. Estimates of effect were therefore expressed as relative risk (RR) with the associated confidence interval (95% CI). After running unadjusted models, we retained all significant risk factors and fitted a final mutually adjusted model. All analyses were performed with Stata statistical software v17.0.At baseline, 4436 women were recruited to the HEAF study, amongst whom 3055 (69%) returned a usable questionnaire at follow-up 5 (2019). The 32 women who reported that they had not yet started the menopause were excluded. In total, 608 women reported starting the menopause within the preceding 10 years, amongst whom 471 were working at the time. Analyses were restricted to the 409 of these 471 women who were in work at the time of the baseline questionnaire and who did not change job over the course of the study, allowing us to be confident that the job they had when they experienced the menopause was the one reported at baseline. Approximately 27% of the sample reported at least moderate problems coping with the menopause at work. The relationship between type of job, physical work demands, psychosocial work demands, and having difficulty with menopausal symptoms at work is summarised in Comparison of the prevalence of each type of menopausal symptoms by job type showed no clear patterns within or between groups. Likewise, when a particular symptom was reported, the proportion of women who described that they had problems coping at work because of their menopausal symptoms was generally similar. In contrast, comparison of the number of symptoms amongst those with no/minor problems , as compared to those with moderate or severe problems  showed higher numbers of symptoms generally amongst those who were most troubled .Estimates adjusted for; difficulties with managing financially; having financial dependants; self-rated health; depression; job security; feeling angry about the job; job satisfaction; and feeling appreciated at work, as well as mutually adjusted, showed that the menopausal symptoms associated with the highest risk of reporting difficulty coping at work were severe headaches, joint aches and pains, and psychological symptoms .Amongst this contemporary cohort of over 400 British women working at the time of their menopause, almost one-third reported difficulty coping with their symptoms at work. Struggling with symptoms at work was not associated with lifestyle or demographic factors but instead with poorer financial circumstances, poorer self-rated health, depression, and with reporting higher numbers of symptoms. Our hypothesis that type of occupation might be associated with the likelihood of specific menopausal symptoms causing more difficulty in the workplace was not substantiated. We found similar prevalence rates for each symptom and similar proportions reporting difficulty coping across the range of occupational groups. Moreover, the impact of different menopausal symptoms did not appear to be affected by physical work demands. In contrast, psychosocial factors at work  were associated with an increased risk of menopausal symptoms impacting coping with work. After adjustment for all other factors, the three symptoms associated with the highest risk of reporting difficulty coping at work were: psychological symptoms , severe headaches and aches and pains in the joints.Our finding that around one-third of working women report significant difficulty coping with their menopausal symptoms at work is consistent with prevalence rates reported in other studies. Albeit with some variation on the precise wording of the question, rates of 25% , 30% 1414, 39.6%Our finding of an association between difficulty coping with menopausal symptoms at work and depression is not new. There is evidence from a number of longitudinal studies that some women are vulnerable to depressive disorder or symptoms during the menopause transition but that this risk attenuates 2–4 years after the final menstrual period . ImportaAn association between work psychosocial stressors and increased difficulties coping with menopausal symptoms at work has been previously reported . StudiesThe current study suggested socio-economic differences in the menopause experience such that women reporting financial difficulties or dependants were more likely to report difficulty coping at work with symptoms. These results are similar to those reported amongst Chinese women in whom lower educational attainment and non-white collar occupation were reported as risk factors for more bothersome menopausal symptoms . EducatiThe findings from this study must be considered within the context of Hormone Replacement Therapy (HRT). It is recognised that HRT use is unequal in society such that women from higher social classes and those with higher levels of educational attainment are more likely to access HRT. In the current study approximately 25% participants reported ever having accessed HRT and ever using HRT was associated with an increased risk of reporting moderate/severe difficulties coping at work because of the menopausal symptoms (OR 1.54). Of course, this reflects reverse causation: those women who are most troubled by menopausal symptoms are those most likely to seek help and to be prescribed hormone therapy. Our finding of more severe work impacts amongst women with poorer socio-economic circumstances may at least partly reflect lack of access to HRT, perhaps because of a lack of health literacy or health self-efficacy and indeed our finding of less impact of menopausal symptoms amongst women with better socio-economic circumstances might reflect better access to appropriate HRT.Some limitations of the study must be acknowledged. Firstly, the cross-sectional data collection about the menopause symptoms limits the possibility of inferring any causal association between variables. There is the possibility of recall bias as the median number of years since the menopause was seven. However, when we refitted the model on the sub-sample of women who reported that they were currently experiencing symptoms, we were reassured to find comparable results, which suggested recall bias did not play an important role. This was to our knowledge one of the first studies to investigate the effect of type of work on the experience of menopause. However, to do this, job titles have been classified into one of nine occupational groups. The SOC2010 classifies job titles into categories without considering job tasks, therefore women within the same classification might be doing quite different occupational tasks. For this reason, we also investigated the burden of menopausal symptoms according to number and type of self-reported physically demanding tasks. On the whole, individuals tend to over-estimate their physical demands at work when compared with formal occupational hygienist assessment, but this should not have affected internal comparisons summarised here. Finally, we used a menopausal symptom list that covered the domains described in the Greene climacteric scale  (symptomA symptomatic menopause causes difficulties coping at work for around a third of working women. Women with depression and poorer financial circumstances are at increased risk and psychosocial, but not physical, work factors are associated. As recently discussed elsewhere , our fin


Microtus ochrogaster) are a socially monogamous and biparental rodent that live in small family groups and are now among the most popular rodent models for studies examining social behavior. Although the social behavioral trajectories of early-life development in prairie voles have been well-studied, how social behavior may change throughout adulthood remains unknown. Here we examined behavior in virgin male and female prairie voles in four different age groups: postnatal day (PND) 60–80, 140–160, 220–240, and 300–320. All animals underwent testing in a novel object task, a dominance test, a resident-intruder test, and several iterations of social approach and social interaction tests with varying types of social stimuli . We found that age influenced neophobia and dominance, but not social approach behavior. Further, we found that young adult, but not older adult, prairie voles adapt prosocial and aggressive behavior relative to social context, and that selective aggression occurs in relation to age even in the absence of a pair bond. Our results suggest that prairie voles calibrate social phenotype in a context-dependent manner in young adulthood and stop adjusting behavior to social context in advanced age, demonstrating that social behavior is plastic not only throughout early development, but also well into adulthood. Together, this study provides insight into age-related changes in social behavior in prairie voles and shows that prairie voles may be a viable model for studying the cognitive and physiological benefits of social relationships and social engagement in advanced age.Several studies using mice have examined the effects of aging on cognitive tasks, as well as sensory and motor functions. However, few studies have examined the influence of aging on social behavior. Prairie voles ( Microtus ochrogaster), which has emerged as a model organism for studying sociality and relevant underlying mechanisms  mimic the potential of encountering a novel prairie vole family while foraging or exploring outside the nest. Because prairie voles are territorial [Although younger subjects were more cautious than older individuals in the presence of a novel object, we observed no effects of age on social approach behavior. Therefore, while it may be in the best interest of a young adult prairie vole to exhibit caution with novel  fitness , it may ritorial , we experitorial  and whenritorial . TherefoDespite a lack of age effect on social approach behavior, we did observe an effect of sex on investigative behavior in the social approach test such that, regardless of age or social context, males investigated stimuli more than females. Consistent with this, recent studies demonstrated that while female prairie voles work harder to access a familiar mate over a novel, opposite-sex conspecific or a familiar conspecific over a novel conspecific, males work equally hard to access any kind of stimuli , 56. TogHere we found that dominance, as assessed by the tube test, varied by age, but only between two age groups, such that the eldest age group (PND300-320) exhibited significantly more losses compared to the second youngest age group PND140-160). This could be a reflection of extremes in our sample such that PND140-160 aged voles may be closer to a stage of peak territoriality, at least compared to voles in advanced age, where losing competitions could result in infanticide of multiple litters of offspring, loss of a partner, or loss of a territory. Notably, the most losses were observed in the eldest age group and the greatest variation in the number of losses occurred within the two older age groups see , suggest. This coIn the present study, we did not observe an effect of age on behavior in the modified resident-intruder test. Thus, in the context of a territorial intrusion, it may be characteristic of prairie voles to engage in aggression and defend their territory regardless of age. However, we observed that both male and female prairie voles in our study were overwhelmingly nonsocial during the modified resident-intruder test and primarily avoided the novel, same-sex conspecific intruder. Although some aggression was observed, low levels may reflect the short duration of our resident-intruder test; due to ethical considerations, Emory veterinary staff required a test no longer than 6 min to prevent potential injury. It is also possible that the lack of aggression may reflect the semi-neutral territory in which the subjects were tested. Although the subject was allowed to “establish residency” for 20 min in the test cage prior to the addition of the intruder, our subjects may have lacked sufficient motivation to defend their territory due to the recency of being placed in the novel cage. However, previous studies in prairie voles have shown that aggressive behavior does not differ during interactions with a novel same-sex conspecific in the homecage or a neutral cage . Furtherappears that prosocial behavior with novel conspecifics may have gradually increased with age and prosocial behavior with siblings may have decreased with age, we found no statistically significant interactions between Age and Stimulus Type, possibly due to the substantial amount of individual variation in our study. Rather, our data suggest that it is not as simple as ‘prairie voles become more or less prosocial with age,’ even within a specific context, but rather that prairie voles calibrate prosocial phenotype in a context-dependent manner in young adulthood and stop adjusting prosocial behavior to social context as they age. We find it somewhat perplexing that male and female prairie voles in young adulthood were not more prosocial with novel opposite-sex conspecifics given that finding a mate and pair bond partner should presumably be a high priority in young adulthood. However, despite our lack of an age effect on approach and investigative behavior in the social approach test, perhaps our results from the social interactions tests indicate that young adult prairie voles are indeed more socially neophobic than their elders. This would align with the object neophobia the youngest age group exhibited in the novel object task.In freely-behaving social interaction tests on neutral territory, we found that male and female prairie voles adjust their behavior accordingly dependent on social context . Not surprisingly, regardless of age or sex, subjects were significantly more prosocial and less aggressive with their familiar, same-sex siblings than they were with either the same- or opposite-sex novel conspecifics see . HoweverX Stimulus Type interactions) on aggression in free-interactions during the social interaction tests or the resident-intruder tests. Instead, our data suggest that the selectivity of aggression changes with age, with male and female prairie voles becoming less selectively aggressive with advanced age.Similar to our findings for prosocial behavior, we also found that aggression profiles differed with age. PND60-80 prairie voles were more aggressive with a same-sex conspecific compared to a sibling and an opposite-sex conspecific. Although the exhibition of prosocial behavior did not differ in interactions with same- and opposite-sex conspecifics for PND60-80 individuals, it may be highly beneficial for this age group to at least suppress aggression when interacting with potential mates given that this age corresponds to the life history transition when prairie voles should be the most receptive to novel members of the opposite sex as they seek a partner to establish a pair bond and reproduce. Conversely, ages PND140-160 and 220–240 were similarly aggressive toward both same- and opposite- sex novel conspecifics. Even though prairie voles can still sire offspring at this age, it may be more likely that, in the wild, they would have already established a pair bond and therefore the need to suppress aggression with novel opposite-sex conspecifics may be waning. Further, our results suggest that in addition to exhibiting an onset of selective aggression with pairbonding , aggressWhy might prairie voles stop altering their behavior in a context-specific manner as they age? One possibility is senility. Perhaps prairie voles lose the ability to discriminate between individuals in advanced age. Although no studies have specifically examined social discrimination in aging prairie voles, a previous study found that olfactory discrimination abilities are preserved in age and are relatively equivalent in 2-, 10-, and 23-month-old mice . Indeed,first litter was sired as PND422 for males and the birth of the first litter for mothers at a maximum age of 180 [If prairie voles do not exhibit impaired social discrimination with age, then a waning expression of context-specific behavior could potentially be due to a decrease in social motivation. Perhaps social encounters with novel individuals are less important because in advanced age, prairie voles are less likely to form pairbonds and produce offspring. However, in labs, prairie vole breeders are typically used for extended periods of time, often beyond the ages that are chosen for subjects. One meta-analysis reported a maximum age at which a e of 180 . This dee of 180 . A simile of 180 . These fIn humans, social relationships tend to improve with age such that older adults generally experience more satisfying and positive social relationships than younger adults . Older aHere we examined behavioral trajectories of aging male and female prairie voles and found that nonsocial neophobia, dominance, and context-dependent social behavior are influenced by adult age. Perhaps most strikingly, our findings suggest that aspects of social behavior  become less selective with advanced age in prairie voles. Whether the waning expression of context-dependent behavior with age is due to a decline in cognitive and/or sensory abilities or a decrease in social motivation remains to be studied. Regardless, our study demonstrates that social behavior is plastic not only throughout early development, but also well throughout adulthood. Notably, our study used virgin adult voles; given that the brain and behavior change with pairbonding in prairie voles –88, it i


Little is known about barriers to and perceptions of participation in the in Women, Infants, and Children (WIC) program in rural Appalachia.To gain a deeper understanding of maternal barriers and perceptions related to WIC participation in rural AppalachiaPregnant women and mothers were recruited in-person and via flyers from WIC offices in three counties in Appalachian North Carolina. Four semi-structured focus groups were conducted between May to July 2018. Each focus group was approximately 60 minutes long and included open-ended questions about the overall WIC experience in rural Appalachia. Focus groups were audio-recorded, transcribed verbatim, and content analysis of transcripts was performed by two trained researchers. Identified themes were discussed and consensus was reached by the researchers to generate final themes for four areas of interest: (1) most valued aspects of WIC program, (2) barriers to program participation and benefit redemption, (3) experiences during appointments, and (4) suggestions for improving experiences in program.The most valued aspects of participation were financial benefits and support/resources provided by WIC staff. In contrast, lack of variety of WIC-approved foods and social stigma were perceived as major barriers to participation and redeeming benefits.This study contributes to a better understanding of the barriers and perceptions related to WIC participation in this geographically and culturally unique area of rural Appalachia. Findings are valuable for informing WIC state-agencies and policymakers whose efforts focus on the identification and development of effective recruitment and retention strategies for WIC-eligible families in rural Appalachia. Rural populations are disproportionately affected by many health inequalities compared to the rest of the nation, including a higher incidence of chronic diseases, higher mortality rates, and lower life expectancies.2Women, infants, and children living in rural communities are particularly vulnerable to these disparities.12The Supplemental Nutrition Program for Women, Infants, and Children (WIC) is a federal nutrition program that serves more than seven million low-income pregnant and postpartum women, infants, and children nationwide.15Despite the WIC program’s benefits, the program has historically been underutilized.22To date, participants’ attitudes and perceptions related to WIC program participation have not been examined in rural Appalachia. The primary aim of this study was to explore maternal attitudes, barriers, and perceptions of WIC participation in the Appalachian Region of North Carolina.This study was part of larger formative research to identify potential intervention foci and develop initiatives to reduce WIC participation barriers and enhance program retention among low-income families in a three-county WIC agency in Appalachian North Carolina. The counties included in this study have stratified degrees of rurality  and population densities .Pregnant women and mothers participating in the WIC program in these three counties were recruited in-person and via flyers. Participants were eligible for focus groups if they met the following inclusion criteria: (1) 18 years or older, (2) enrolled and/or has a child or children currently enrolled in the WIC program, (3) the primary person who redeems WIC food benefits/attends clinic visits, and (4) speaks English. Non-English speakers were excluded due to lack of a trained translator to conduct focus groups in another language. The study protocol and procedures were approved by the University of North Carolina’s Institutional Review Board.In each county, a researcher was on-site in the WIC clinics on two separate days for in-person recruitment. Since families receive WIC benefits on site only every 3 months, different days and times of the week were targeted to increase diversity of potential participants. If a participant met all eligibility criteria, the researcher obtained the participant’s contact information, and a focus group was scheduled via phone. When the researcher was not available for recruitment on-site, WIC clerks handed out recruitment flyers and interested participants were encouraged to contact the researcher directly via phone or email. Recruitment flyers were also posted in common areas of each health center . To further increase the diversity of participants recruited, WIC staff mailed recruitment flyers and letters along with other regular WIC mail to an additional 55 participants. A text message reminder was sent to all participants the day before the scheduled focus group to confirm their attendance.Tell me about what motivates you to participate in the WIC program.” and “If you could change one thing about the WIC shopping experience, what would you change?”A focus group guide was developed specifically for the current study to explore participants’ perceptions and experiences related to their participation in the WIC program. The guide followed a semi-structured questionnaire formatThe guide was reviewed by three nutrition researchers with expertise in nutrition behavior in low-income families with children, one psychology researcher specialized in low-income families with children, and six WIC staff members who have daily experience with the program’s participants. The original guide was revised using the input and feedback from the reviewers.Focus groups were conducted by a trained researcher at local public libraries or a hotel conference room. Each focus group lasted approximately 60 minutes and was audio-recorded. Participants reviewed an IRB-approved informed consent form and provided verbal consent upon their arrival to the focus group. Participants used only their first names throughout the focus group and filled out a brief questionnaire with sociodemographic information after the focus group. Participant incentives included a $20 gift card and light refreshments during the focus group.https://www.temi.com/), and reviewed by the primary researcher to ensure accuracy and detail of the data.Field notes were completed immediately following each focus group to document overall impressions, main themes discussed, and any other information that could be relevant for data analysis. Audio recordings were transcribed verbatim utilizing 2020 Temi, speech recognition software  were conducted with a total of 15 mothers and pregnant women. Demographic characteristics of the participants are presented in The content analysis revealed several themes that emerged during the focus groups around the four areas of interest. The main themes are described below and selected quotes for each theme are presented in Financial benefits were the most valued aspects of WIC participation (Theme 1A). Participants noted that WIC helped offset the costs of buying groceries for their families and thus allows for the allocation of money to other household expenses. Provision of WIC-approved foods and/or formula and/or breastfeeding supplies  were also highly valued. All participants with breastfeeding experience reported they would not have been able to afford to purchase a breast pump without participating in WIC. Participants felt that WIC provided much more than “just food.” Referrals to other healthcare providers and other sources of food assistance were additional valuable support/resource benefits reported (Theme 1B). Prenatal and breastfeeding support and education were other frequently reported and highly valued nonfinancial benefits.efficiency of clinic visits, noting the convenience and flexibility of scheduling a WIC appointment and short wait time to be seen (Theme 2A). A caring and nurturing approach by staff was another positive aspect of the WIC office experience (Theme 2B). Participants reported staff consistently answered their questions, addressed their concerns, and made them feel valued and heard. Several negative aspects of office visits also emerged. Discrepancies in nutrition recommendations between the WIC nutritionist and pediatricians were noted, although this theme was not consistent across all focus groups (Theme 2C). Coupling this discrepancy was the feeling that staff sometimes employed a high-pressure approach when providing nutrition education, which further contributed to a negative office experience (Theme 2D). Notably, participants reported feeling pressured by WIC staff to prove their ability to breastfeed and felt this practice could discourage participation in the program.The positive experiences were consistent across the district. Participants highly regarded the Poor labeling and inconsistency/variability of WIC-approved items across grocery stores were cited as major barriers (Theme 3A). Poor labeling included both a general lack of labeling in some stores and labeling with very small font in other stores, which made it difficult to identify WIC-approved items. Participants reported problems redeeming some WIC-approved items  with issues varying by the grocery store (Theme 3B). General lack of variety of WIC-approved foods locally available to purchase (i.e. fruits and vegetables (FV) and whole grains) was another significant barrier (Theme 3C). Participants in the smaller and more rural counties reported the most limited variety and availability in their area. A limited number of grocery stores was an additional barrier discussed during the focus groups (Theme 3D). Delays at checkout due to having to separate WIC foods from non-WIC foods emerged as one of the biggest barriers to benefit redemption (Theme 3E). Participants noted the checkout experience frequently evoked feelings of anxiety and embarrassment, a direct result of social stigma, which emerged as the most frequently reported perceived barrier to WIC benefit redemption (Theme 3F). Participants felt that WIC and other federal and state assistance programs for those in need were generally perceived negatively within their communities. Some participants reported they intentionally avoided high volume shopping hours and/or shopped in neighboring counties to avoid being recognized and/or minimize judgment from others.Participants reported several barriers related to redeeming their food benefits. improving the available food packages (Theme 4A), suggestions for enhanced nutrition education services (Theme 4B), and suggestions for expanded community outreach, knowledge, and awareness of the WIC program (Theme 4C).Many suggestions were made by the participants on ways to improve their WIC experiences within three main topics: Participants reported receiving too much milk, yogurt, and/or cheese and cereal and thus frequently not fully utilizing these benefits (Theme 4A). General dissatisfaction with the juice benefit was apparent, with participants stating they would prefer to have more FV instead of juice. Greater flexibility in whole grains benefits was also desired .Enhancing and expanding nutrition education within the program also emerged as a suggestion for improving the WIC program and its services (Theme 4B). Participants expressed interest in post-partum weight loss education, reporting that they felt their needs were overlooked after their babies were born. Additional education on current food packages (i.e. existing flexibility of packages) and availability of various WIC-approved foods at different stores in each respective community was also suggested.expanded community outreach, knowledge, and awareness of the WIC program was an additional suggestion for improving the program (Theme 4C). General lack of awareness of WIC services was also reported. Many participants indicated they first heard about WIC by chance via word of mouth from someone who had personal experience using WIC, or at the local hospital after delivering a child. A few participants were aware of WIC services due to their college courses. Another major barrier to WIC program enrollment was confusion about eligibility criteria. Most participants did not know women might be eligible for WIC services starting during pregnancy, thus many of them did not enroll until after their first child was born, despite being aware of the WIC program. Confusion about income and/or other adjunctive eligibility criteria also emerged as major barriers to seeking enrollment (Lastly, Even though WIC participation is associated with many improved health outcomes among women, infants, and children nationwide,Consistent with previous work,Some of the findings on barriers to WIC participation/benefit redemption are consistent with previous larger-scale investigations in various regions of the nation. Poor labeling of WIC-approved foodsThe most pervasive barrier to participation reported in the current study was social stigma. In other larger studies, social stigma has been perceived as having a mild to moderate impact on participation,23In this context, it is important to consider the influence of the unique culture of the Appalachian Region on the perceptions and experiences of social stigma. This region is largely conservative and known for valuing individualism and self-reliance as well as religious fundamentalism and fatalism.The confusion about eligibility criteria, a known barrier to WIC participation,This study has several major strengths but also limitations that must be noted. A key strength is that to the authors’ knowledge, it is the first study of its kind to explore barriers and perceptions of the WIC experience from the perspective of WIC mothers and pregnant women in rural Appalachia. Further, recruitment of participants from a WIC agency that includes three bordering counties with stratified degrees of rurality allowed for the examination of a broader range of attitudes, barriers, and perceptions surrounding the WIC experience in rural Appalachia, as some experiences varied by county. The in-depth, qualitative nature of this study also allowed for mothers to share their own experiences in a focus group format, which allows for a deeper understanding of the WIC experience in this region. A few limitations should also be noted. First, because of resource limitations, non-English speakers were not included despite having some Hispanic families enrolled in WIC in the region. Secondly, mothers experiencing transportation barriers may not have signed up to participate. Third, the majority of participants in this study were non-Hispanic white and all participants had at least some college education, which may have influenced their decision to participate. Considering the majority of WIC participants nationwide have a high-school education,The WIC program can be effective in reducing nutrition-related inequalities experienced by low-income families with young children in the Appalachian Region. However, our findings show that rural families have unique experiences when participating in WIC and are faced with specific barriers that need be addressed in order to increase WIC enrollment and reduce program attrition of families in this region. This study provides insight into the WIC experience in rural Appalachian North Carolina and lays the foundation for further investigation. More targeted efforts that take into consideration regionally inherent structural, cultural, and economic challenges are needed to fully maximize the broader societal benefits of WIC participation in the region. Specifically, WIC agencies should focus on enhancing and/or creating partnerships and collaborations with local pediatrician and obstetrician offices, religious organizations, food banks, and grocery stores to expand awareness and knowledge of WIC services while reducing social stigma among community members. Additional research is also warranted to fully understand perceptions and attitudes related to WIC’s mission among various community stakeholders that serve low-income families with young children in rural Appalachia.What is known about this topic? Although participation in WIC has been associated with favorable nutrition-related health outcomes in low-income families, WIC-eligible families continue to face a number of barriers to participation.What is added by the report? Lack of variety/availability of WIC-approved foods and social stigma were perceived as major barriers to participation and redeeming benefits among WIC participants in rural Appalachian North Carolina.What are the implications for future research? Findings are valuable for informing WIC state-agencies and policymakers whose efforts focus on the identification and development of effective recruitment and retention strategies for WIC-eligible families in rural Appalachia. A better understanding of what healthcare professionals in this region of Appalachia know about the WIC program and how they perceive WIC services is needed to identify more effective ways to increase awareness and utilization of WIC services in this region.