The corporate political activities of harmful industries, including the use of agnogenic (ignorance or doubt producing) practices and the construction of dystopian narratives, directed at influencing policymaking are well documented. However, the use of agnogenic practices by industry-funded organisations who deliver industry-favoured education-based measures remains unexplored. This study aims to build understanding of this by analysing three UK gambling industry-funded youth education programmes that represent key policy responses to gambling harms.Using a published typology of corporate agnogenic practices the ways that evidence is used within the programmes’ resources to legitimise their content and implementation were analysed. Programme evaluations and claims about the programmes’ evidence base and effectiveness were also analysed.Agnogenic practices, including confounding referencing, misleading summaries and evidential landscaping, that resemble those adopted by harmful industries are used within gambling industry-funded youth education programmes and by the charities that oversee their delivery. These practices serve corporate interests, distort the limited evidence in support of youth gambling education measures, and legitimise industry favoured policies.This novel study demonstrates that agnogenic practices are used to construct utopian narratives that claim that gambling industry-favoured youth education programmes are evidence-based and evaluation-led. These practices misrepresent the literature and evaluation findings and may undermine effective policymaking to protect children and young people from gambling harms.• Gambling industry-funded education programmes warrant greater scrutiny and conflicts of interest need to be addressed.• The methods and findings of this study are of relevance to other contexts and areas in the field of the commercial determinants of health given other harmful industries adopt similar approaches.


Editorial on the Research TopicAdvancing the understanding of surgical management for degenerative spine conditionsDegenerative spine conditions are common in adults, especially among the elderly. In parallel with the aged tendency of population worldwide, the prevalence of degenerative spine diseases has been increasing. There has also been an increasing trend in spine surgery worldwide –3. HowevQian et al. that may because the laminoplasty releases dorsal spinal cord from compression in pinching cervical spondylotic myelopathy (PCSM). Yang et al. took advantage of finite element analysis of CT images and found the maximum stress in involved segments of cervical spondylotic myelopathy (CSM) was higher compared with the control group. Two papers summarized theoretical knowledge of certain spine diseases. Xu et al. gave a detailed and authoritative review for ponticulus posticus, including the epidemiology, pathology, anatomy, clinical presentation, radiographic examination and surgical significance of ponticulus posticus. Mei et al. gave us a rare case of camptocormia related to Parkinson's disease and reviewed the literature on camptocormia.Learning the basic knowledge of spinal disorders helps to give us an overall understanding of surgical treatment. Several papers in this Research Topic gave us their understandings of pathogenesis of some spine diseases. The reason why cervical sagittal curvature of certain patients will be lordotic after laminoplasty is unclear. As pointed out by Wasinpongwanich et al. in their systematic review and meta-analysis, summarized fusion rate, operative time, clinical outcomes, complications  for transforaminal lumbar interbody fusion (TLIF) vs. other techniques used in lumbar spine diseases. Focusing on elderly patients with single-level thoracolumbar severe osteoporotic vertebral compression fracture (sOVCF), Zhou et al. provided evidence for the effects of percutaneous kyphoplasty (PKP) with vs. without posterior pedicle screw fixation (PPSF) on long-term spinal sagittal balance. Due to limited guideline information on whether indirect decompression is sufficient after oblique lumbar interbody fusion (OLIF), Tseng et al. compared the effectiveness of the indirect decompression by OLIF with direct posterior decompression among lumbar foraminal stenosis patients. Radiofrequency denervation, as a common interventional treatment for chronic low back pain, has different emerging types such as pulsed radiofrequency denervation. In their systematic review, Li et al. comprehensively reviewed literature on radiofrequency denervation therapy in treating facet joint-derived chronic low back pain and compared efficacy of different radiofrequency denervation interventions using network meta-analysis.A number of papers in the current Research Topic focused on comparing different surgical procedures used in spine surgery. Chen et al. evaluated the learning curve of UBE using the cumulative summation (CUSUM) method analysis.Understanding the learning process of surgical techniques is beneficial to surgeons who hope to master one surgical technique. For the past few years, unilateral biportal endoscopic (UBE) has become a popular technique for spinal surgery. However, even for skilled spinal surgeons, there may be obstacles in the learning process of UBE technology. To this end, Briguglio et al. tried to develop a hemoglobin-based prediction model to predict long-term recovery after spine surgery but regrettably, this model may not be reliable due to the low specificity. Nevertheless, as indicated by Briguglio et al. preoperative hemoglobin, interestingly, is one of the key laboratory biomarkers to predict long-term recovery after spine surgery. Identifying prognostic factors for patients who received spine surgery is also of great importance. By finding out factors which could provide prognostic information for patients, we may forecast the future outcomes in patients with a particular health condition and thus choose more suitable treatment under a specific situation. The risk factors for postoperative shoulder imbalance are rarely reported in adult scoliosis (AS). Hence, Ke et al. performed a detailed assessment of risk factors related to radiography in AS patients who underwent correction surgery. Deng et al. gave a comparison of sagittal balance and functional outcomes in lumbar fracture surgery patients using different intermediate pedicle screws with different insertion depth. Wei et al. examined risk factors of bone graft nonfusion for spinal tuberculosis patients who underwent lesion removal, bone graft fusion and internal fixation.Prognosis research is of great importance in the context of current spine surgery. Several papers published in this Research Topic developed prediction model and investigated prognostic factors in different kinds of spine surgery. Clinical prediction models have plenty of applications in clinical practice. For instance, clinical prediction models help us to decide whether we need further testing, whether we need to start a treatment and which treatment need to be performed . BriguglJin et al. compared the subsidence rate in zero profile anchored spacer (ROI-C) and conventional cage and plate construct (CPC) in patients undergoing anterior cervical decompression and fusion (ACDF). Cases series by Florence et al. provided eight cases who had hardware complications after placement of interspinous process devices (IPDs) and gave us experience in management of high risk IPD patients.Complications after surgery also deserve more attention. Focusing on postoperative cage subsidence, a common complication after spine surgery, Xu et al. developed a new surgical plan for adults with tibial-eminence fracture (TEF) and assessed the clinical effectiveness of day case arthroscopic-surgery treatment. Interestingly, thromboelastography (TEG) markers could forecast the occurrence of ecchymosis after total knee arthroplasty (TKA), as found by Chen et al.This Research Topic also included papers related to other orthopedic surgery, which give an additional view for spine surgery. For instance, We sincerely thank all authors who contributed to the current Research Topic “Advancing the Understanding of Surgical Management for Degenerative Spine Conditions”. We appreciate the reviewers' valuable comments and constructive suggestions. Also, we express our gratitude to the editorial team for their support.We unfeignedly hope that articles in this Research Topic will help surgeons make the right decisions and inspire researchers to give a further exploration of surgical management for degenerative spine conditions.


Botrytis, Colletotrichum, and Fusarium.Crop plants are constantly exposed to diverse biotic stressors during their lifetime. Fungal pathogens represent a predominant biotic stress of crops and account for 80-85% of known diseases leading to significant yield losses. Host plant resistance against fungal pathogens is due to diverse factors such as plant genetic background, physiological status, agroecological, and environmental conditions. In addition, the microbiome associated with host plants has also been shown to contribute to resistance by producing metabolites that modulate host plant defense pathways or exhibit antimicrobial properties. The advancement in next-generation sequencing (NGS) technology for genome/RNA sequencing and modern omic approaches such as proteomics, metabolomics, and interactomics have profusely helped to define host plant resistance mechanisms. These technological advances have made possible introgression of resistance traits into agronomically important varieties by traditional or molecular breeding. Recently, the application of highly sophisticated biotechnological tools using RNAi or CRISPR-Cas9-based gene editing has enabled us to precisely manipulate the integration and expression of key genes for enhanced host resistance. This special issue compiles articles that highlight mechanisms underlying host plant-fungal interactions that govern susceptibility or resistance to fungal pathogens including Botrytis cinerea (B. cinerea) negatively impacts strawberry production worldwide. The fungus preferentially infects flowers and fruits of strawberry. Using B. cinerea resistant and susceptible cultivars and global mRNA sequencing, Xiao et al. demonstrated higher expression of defense-related genes and lower expression of genes associated with cell wall degrading enzymes and peroxidases in the resistant cultivar during early stages of infection. The authors also showed increased expression of calcium signaling pathway related genes namely CPKs, RBOHDs, CNGCs, and CMLs and genes associated with jasmonic acid, auxin, and phenylpropanoid metabolism in the resistant cultivar. The work presented here could be useful for future breeding efforts or transgenic manipulation of candidate genes to improve gray mold resistance in strawberry.Gray mold disease in strawberry caused by the necrotrophic fungus B. cinerea, Zhao et al. delineated the molecular basis of resistance. Using resistant and susceptible genotypes and a combination of tools including gene expression, quantification of metabolites, and microscopy, the authors dissected leaf-associated factors in woodland strawberry potentially contributing to resistance against the fungus. Higher basal (in absence of the fungus) expression of resistance related genes rather than induction of genes in response to the fungus was observed in the resistant genotype. Metabolites such as total phenolics, total flavonoids, glucose, galactose, citric acid, and ascorbic acid were positively correlated with B. cinerea resistance, whereas H2O2 and sucrose were negatively correlated with resistance. The authors suggested higher innate antioxidant profile of leaves as one of the key factors contributing to resistance against the fungus.In another study addressing strawberry leaf resistance against Hordeum vulgare L. var. nudum), Tibetan hulless barley grown in higher elevation regions, is not fully understood. Using genome and transcriptome mining through bioinformatics, Wang et al. demonstrated the role of specific members of the TLP gene family in biotic (powdery mildew) and abiotic  stress tolerance. Analysis of promoter regions of this gene family showed presence of putative transcription factor binding motifs associated with growth and development, hormone signaling, light and stress responses. Gene expression analysis using qRT-PCR validated the induction of specific members of TLPs in response to sodium salicylate and methyl jasmonate treatments. The work presented here provides future opportunities for crop improvement in Qingke which is a staple crop in Tibet.In plants thaumatin-like proteins (TLPs) have been implicated in a wide range of physiological processes including stress response and growth and development. The role of this gene family in Qingke  is an economically important tree species and highly susceptible to the fungal pathogen Colletotrichum fructicola. Zheng et al. dissected the role of specific plant secondary metabolites in resistance against this fungus using C. paliurus resistant and susceptible cultivars. Through multiomic approaches namely mRNA sequencing and metabolomic analyses, the authors demonstrated that early induction and reprogramming of the flavonoid biosynthetic pathway potentially contribute to resistance to C. fructicola. The information presented here provides valuable information on biomarker/s for future resistance breeding in C. paliurus and/or using natural flavonoid extracts from a resistant cultivar as an antifungal treatment against this fungus.Wheel wingnut . The authors found that faba bean–wheat intercropping under field conditions significantly improved Fusarium wilt disease severity in comparison to monoculture of faba bean plants. Reduction in cellular contents of H2O2 and O2 accompanied by increased expression and activities of superoxide dismutase and catalase enzymes in the roots of faba bean plants were observed when intercropped with wheat. In addition, reduced benzoic acid and cinnamic acid in the rhizosphere soil of faba bean plants improved the stability of root cells. The authors used a reverse approach and showed that exogenous application of benzoic acid and cinnamic acid to the roots of faba bean plants increases Fusarium wilt symptoms under greenhouse conditions. This demonstrates the role of allelopathic compounds in the rhizosphere of faba bean crop in resistance to Fusarium wilt.Overall, the work presented in this volume advances our understanding towards plant-fungal interactions and sets a good foundation for future breeding approaches to improve crop resistance to fungal pathogens.All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.


Phaeodactylum tricornutum (UTEX 466) using different loadings of fungal pellets (Aspergillus sp.) and model the process through kinetics and equilibrium models. Active P. tricornutum cells were not required for the fungal-assisted immobilization process and the fungal isolate was able to immobilize more than its original mass of microalgae. The Freundlich isotherm model adequately described the equilibrium immobilization characteristics and indicated increased normalized algae immobilization  under low fungal pellet loadings. The kinetics of algae immobilization by the fungal pellets were found to be adequately modeled using both a pseudo-second order model and a model previously developed for fungal-assisted algae immobilization. These results provide new insights into the behavior and potential applications of fungal-assisted algae immobilization.Immobilizing microalgae cells in a hyphal matrix can simplify harvest while producing novel mycoalgae products with potential food, feed, biomaterial, and renewable energy applications; however, limited quantitative information to describe the process and its applicability under various conditions leads to difficulties in comparing across studies and scaling-up. Here, we demonstrate the immobilization of both active and heat-deactivated marine diatom  The insights and modeling techniques demonstrated here will help to provide industrially relevant benchmarks for the immobilization of other species of commercial or environmental interest and provide necessary data for future techno-economic and life cycle assessments.


Social isolation is prevalent among community dwelling older adults. Low income older adults living in subsidized housing may have increased risk for social isolation. To examine resident experiences and perspectives relating to their social connections during the COVID-19 pandemic, we conducted semi-structured interviews with 13 older adults (62+) who are English, Spanish, and Mandarin speaking recruited from a large non-profit affordable housing organization with communities in 22 states. Twelve housing communities were identified based on distributions of socio-demographic factors and prevalence of self-reported social isolation l in the housing community’s annual survey of residents in order to maximize site diversity. We used qualitative thematic analysis methods to examined participants’ views about their social connections before and during the COVID-19 pandemic, as well as their personal and the housing community’s strategies to mitigate experiences of social isolation. Emerging themes include loss of common facilities and opportunities to socialize with other residents due to COVID-19 restrictions, and increased use of technology to stay connected.


Neighborhoods are diverse and may or may not present opportunities for stress reduction or social engagement depending on their qualities. Based on the stress connectome , psychosocial stress may accelerate cognitive aging, which explains place-based disparities in cognitive function. This study examines two attributes of the neighbourhood environment, and their potential to influence cognitive function through semantic fluency.Using aggregated baseline  data from N=1,010 neighborhoods with 5 or more respondents in the Canadian Longitudinal Study on Aging, we examined the effects of neighborhood greenness and cohesion on aggregates of age-, sex-, and education-adjusted cognitive test scores. Participants were community-dwelling adults aged 44 and above. Semantic fluency was assessed using the Animal Fluency Test (AFT). Delayed recall was assessed using Rey’s Auditory Verbal Learning Test (RAVLT), whereas executive function was assessed using Mental Alternation Test (MAT). Neighborhood qualities were found to affect delayed recall  and executive function  through semantic fluency . Semantic fluency fully mediated the effects of neighborhood attributes on cognitive function. Further stratifying these neighborhoods by socioeconomic status showed that cohesion has stronger effects in poorer neighborhoods (B indirect=.104) than richer neighborhoods (B indirect=.066). The effect of greenness was no longer significant upon stratification. Neighborhoods offer an important social arena for adults in mid- and late-life to practice conversing, especially in poorer neighborhoods, which improves cognitive function. Creating opportunities for socialization by improving cohesion and neighborhood parks may reduce place-based disparities in cognitive health. Causality remains to be ascertained.


Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders. Conditioned fear inhibition is achieved by the repeated presentations of the conditioned stimulus in the absence of the unconditioned stimulus. This fear extinction process is critical for fear reduction in the aftermath of trauma exposure or when exposed to fear- and anxiety-inducing stimuli. Failure to appropriately extinguish fear could contribute to the maintenance of anxiety-related symptoms, which is thought to characterize posttraumatic stress disorder (PTSD) and anxiety disorders , 2. PavlMost human neuroimaging studies have yet to establish a connection between cognitive/attention networks and the subjective measures of fear and anxiety. Recent studies started to emerge in support of the LeDoux-Pine concept. For example, meta-analyses revealed the engagement of multiple cortical regions during the fear conditioning and extinction tasks , but theIn this study, we examined the dynamic changes of large-scale FC across extinction learning in healthy individuals and in patients diagnosed with anxiety disorders or PTSD. We estimated whole-brain connectivity of participants during different timepoints of extinction learning, compared the FC change between groups, and evaluated the relevance of extinction-induced FC changes to various fear- and anxiety-related clinical metrics. Based on our previous study , and givWe analyzed data from a total of 338 individuals (see Supplementary Methods). Of those, 77 were healthy controls (HC), 91 were diagnosed with anxiety disorders (AX), 81 were diagnosed with PTSD, 89 were trauma-exposed non-PTSD controls (TENC)  procedure , r = 0.48, p < 0.001), but not in the AX group  or the PTSD group . Steiger’s Z test confirmed that the HC group showed significantly higher correlation than the other two groups . A significantly positive correlation between ΔFC and vmPFC activation was also observed in the HC group using the network identified with HC vs. PTSD  group as a control group, we conducted additional FC analyses comparing the PTSD to TENC. These additional analyses mostly replicated the results of HC vs. PTSD analyses (see Supplementary Results for details); revealing a significant network component that mainly involved connections between the DMN with other networks , supporting the robustness of the identified canonical variate. We then calculated the canonical loadings to examine how the individual clinical measure and connectivity contributed to the canonical variate  in the HC and AX groups . The canonical loadings indicated that the symptom measure positively contributed to the clinical variate, while ΔFC negatively correlated with the connectivity variate  in the TENC and PTSD groups  and patients diagnosed with anxiety disorders (AX) or PTSD. From early to late extinction learning, HC exhibited an increase in FC that was specific to the conditioned cue. The AX and PTSD groups exhibited widespread FC impairments during extinction learning. The relative FC reductions in patient groups were predominantly in the interactions between the default mode network (DMN), frontoparietal control network (CON), somatomotor network (SMN), and attention networks (DAN/VAN). The extinction-induced FC changes were predictive of vmPFC activation during extinction recall only in the HC group. FC changes during extinction learning positively and negatively correlated with FC during recall in the HC and the AX groups, respectively. Finally, extinction-induced FC was associated with subjective measures of fear- and anxiety-related clinical metrics.Animal literature shows that learning-induced plasticity can change both neural activity and neuronal synchronization . Neural Prior fear extinction studies have focused predominantly on neural circuits associated with expression and inhibition of conditioned threat responses. The conscious awareness of fear, and the feeling of no longer being afraid, would require multiple cognitive processes, including perception, attention, conscious awareness, and memory construction. These multi-level processes are likely to require coordinated interactions between distributed brain regions . A recenThe distinct dysfunction in some networks and the partial overlap in some others across the AX and PTSD groups suggest both divergent and shared mechanistic impairments pertinent to fear inhibition across these psychopathologies. While there was an overlap in the FC dysfunction across multiple brain regions between the patient groups, the dlPFC—a region known for its contribution to cognitive control and regulation –44, appeWe observed a positive correlation between extinction-induced ΔFC  and vmPFC activation during memory recall only in the HC group. The vmPFC plays a key role in inhibiting threat response , 20, 49.We specifically focused our analyses on the connectivity during CS+ processing since our previous study on healthy controls showed that connectivity during CS+ processing increased from early to late extinction learning, and predicted the magnitude of extinction memory . The ideWe observed abnormal connections extensively involved CON and DMN in the PTSD group when comparing it with either the non-exposed controls or trauma-exposed controls. This result suggests that the connectivity alterations in the PTSD group are not merely a result of the traumatic exposure. There is evidence showing that traumatic exposure per se may alter activation and functional connectivity , 53, 54.The dynamic nature of extinction learning-induced neural plasticity is overlooked to some degree in prior studies as many neuroimaging studies average functional brain activation across extinction learning. However, a few prior studies suggested the dynamic changes of activation during the fear conditioning and extinction paradigm in PTSD and healthy participants , 31. SpeSupplemental material


Positive affect is important for physical health, well-being, and relationships. Yet, most studies of dementia care dyads have focused on negative outcomes, such as depression and caregiver burden. We present findings from studies that address this important research gap. The first two speakers present findings from actor partner interdependence models using secondary data from a randomized controlled trial of persons with early-stage dementia (PWD) and their spouses. Specifically, Dr. Monin will show that actor quality of life is significantly related to positive affect cross-sectionally, controlling for functional status of each partner and PWD behavioral symptoms. Ms. Piechota will present longitudinal findings demonstrating that when spouses were high in difficulty regulating emotions, the PWD’s positive affect decreased over three months, controlling for intervention arm and covariates. The second two speakers will present findings from two different studies of persons living with behavioral-variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and controls that engaged in laboratory conflict discussions. Dr. Brown will show that caregivers of individuals with bvFTD reported greater decreases in positive emotion across the discussion relative to caregivers of individuals with AD and language variants. She will also discuss how caregivers who reported greater decreases in positive emotion had higher levels of depressive symptoms, controlling for their partner’s diagnosis and level of cognitive impairment. Finally, Dr. Chen will provide evidence that bvFTD caregivers had lower emotional well-being according to the SF-36 than AD caregivers and controls, and this effect was fully mediated by bvFTD caregivers' lower positive emotional connections.


Increasing travel times to the nearest diagnostic facilities and cancer centers are correlated with decreasing prevalence of breast cancer diagnosis and increasing stage of cancer at diagnosis. Moi Teaching and Referral Hospital (MTRH), in Uasin Gishu County, houses the only public cancer center in western Kenya. A MTRH program, the Academic Model Providing Access to Healthcare Breast and Cervical Cancer Control Program (ABCCCP) hosted health fair breast cancer screening events and mentored nurses at local health facilities to complete clinical breast exams (CBEs). The objective is to understand the effect of the ABCCCP in reducing geographic barriers for breast cancer screening/early diagnosis.This is a retrospective review of the 61,392 patients who underwent breast cancer screening at a ministry of health facility in western Kenya from 2017-2021. ABCCCP hosted health fairs targeted at communities and mentored nurses at health facilities to complete clinical breast exams (CBEs) to target individual patients. Facility distances from MTRH were mapped via Google Maps. Descriptive analyses were performed to a significance of α < 0.05.Two-thirds of the screening/early diagnosis CBEs occurred in five of the 22 counties in western Kenya: Busia, Uasin Gishu, Trans-Nzoia, Bungoma, and Kakamega. However, these five counties only had 25% of all ABCCCP screening sites in western Kenya. Only Uasin Gishu and Kakamega provided chemotherapy while Busia and Trans-Nzoia had additional programming promoting preventative healthcare through integration of community health volunteers. In these five counties, no association between the distance of the ministry of health facilities from MTRH and number of CBEs completed existed.ABCCCP programming reduced some geographic disparities in breast cancer screening/diagnosis in the top five counties. It may be result of the number of mentored nurses and health fair events. Further work should be completed to understand if a relationship between geographic distance from MTRH and the stage and treatment patterns of these patients is also reduced by ABCCCP.


Research from across the globe has consistently shown that young sexual and gender minority individuals  are at a higher risk for depression, anxiety, and suicidal thoughts and behaviors when compared to heterosexual youth, including during early childhood and later adolescence. A sizeable body of research has attributed the elevated risk to increased exposure to specific social stressors related to navigating a stigmatized minority identity, including stressors such as victimization and other interpersonal and social difficulties in, for example, the school environment. Yet, relatively less is known about the early developmental timing of such disparities in childhood and how LGBT+ youth navigate school climates. As a sensitive developmental period, childhood and adolescence may be a particularly challenging time for sexual and gender minority youth to navigate cisnormative and heteronormative school contexts. Exposure to oppressive norms, particularly in school environments, has only recently become the subject of research. Additionally, research has been limited on how supportive school climates may be protective but stigmatizing school environments may drive LGBT+ trajectories towards suicidal behaviors and shape how they may navigate self-disclosure of cooccurring identities and mental health status in school settings, particularly when such stigmas may prevalently intersect. This workshop aims to further explore these novel aspects around developmental and school-based risk and protective factors shaping the mental health of sexual and gender minority children and adolescents. This workshop includes five empirical presentations that span from examining the developmental timing of mental health disparities, the role school-based experiences play in shaping and driving these disparities, to how sexual and gender minority youth may navigate their school context and how supportive climates may be protective for mental health. First, Arjan van der Star will present longitudinal evidence on how sexual identity formation precedes the onset of sexual orientation-based mental health disparities and the role that peer difficulties play in driving these as early as pre-teen years. Next, Niolyne Jasmin Bomolo will present findings from a qualitative study that unravel how school-based experiences shape individual trajectories toward suicidal attempts among LGBT+ adolescents. Third, Wouter Kiekens will explore how normative cultures in school environments may drive sexual attraction-based mental health disparities among a large sample of adolescents. Fourth, Lourdes Cantarero Arévalo will present findings on how LGBT+ adolescents living with mental conditions navigate self-disclosure in school environments. Finally, Sandra Sevic will present results on how supportive school environments may be protective for gender minority mental health.• Negative school-based experiences put sexual and gender minority youth at elevated risk for adverse mental health as early as middle childhood.• Intersecting stigmas around minority identities and mental health problems may further complicate how sexual and gender minority children and adolescents navigate their school environments.


In recent years, targeting tumor specific metabolism has gained an interest as a promising therapeutic strategy. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is highly prevalent in ovarian carcinoma patients and contributes to elevated mitochondrial metabolism in ovarian tumor models. The SDHA overexpressing tumor cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation in mitochondria to meet their energy requirements. Further, we found that those cells are particularly vulnerable to deprivation of essential nutrients such as glucose and glutamine, which led to a substantial reduction of ATP yield. Lastly, we identified an anti-metabolic compound shikonin, which demonstrated a potent anti-tumor efficacy against SDHA overexpressing ovarian cancer cells. Overall, we strive to advance scientific knowledge by uncovering the previously unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which holds untapped opportunities for therapeutic intervention.We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention. The reprogramming of cellular metabolism is a hallmark of cancer allowing tumor cells to survive and proliferate. The Warburg effect is an established signature of cancer metabolism and refers to the observation that tumor cells preferentially use glucose via glycolysis pathway rather than oxidative phosphorylation (OXPHOS) in mitochondria for energy production . The relSDHA gene amplification or overexpression is highly prevalent in ovarian carcinoma patients  compared to other tumor types, which indicates its potential importance in reprogramming of ovarian cancer metabolism.To gain a greater insight into the ovarian cancer metabolism, we interrogated metabolic phenotypes of patient-derived xenografts (PDXs) developed from patients’ ovarian tumors . We usedSuccinate dehydrogenase (SDH) also known as mitochondrial complex II, couples oxidation of succinate to fumarate with reduction of ubiquinone to ubiquinol, thus directly connecting the mitochondrial electron transport chain (ETC) with the tricarboxylic acid (TCA) cycle . SDH conIn this work, using various in vitro and in vivo ovarian cancer models, we investigated the biological consequences of SDHA overexpression and its impact on tumor phenotype. Our findings revealed that SDHA overexpression is associated with the improved ability of cells to survive and generate colonies in anchorage-independent conditions. This is an important feature of metastatic ovarian tumor cells that are able to survive and spread in peritoneal fluid (ascites) within the abdominal cavity. Further, we showed that the overexpression of SDHA enhanced ovarian cancer metabolism reflected as increased mitochondrial respiration and ATP production rate. Lastly, we performed a drug screening and identified an anti-metabolic compound shikonin known to disrupt glycolysis and amino acid metabolism ,20. We sAltogether, our study demonstrated that SDHA upregulation frequently occurs in ovarian cancer and contributes to reprogramming of energy metabolism towards highly metabolically active phenotype. Importantly, we showed here that SDHA overexpressing tumor cells can be effectively targetable by anti-metabolic compounds such as shikonin, which represents a new opportunity for therapeutic intervention in ovarian cancer.2 and 95% O2 atmosphere. Cell lines were tested for Mycoplasma by Idexx BioAnalytics and were found negative for any contamination. Human fallopian tube tissues and established PDX tumor models were obtained from the PDX-PCT core facility at OMRF ..29]. We In conclusion, this study demonstrated that the SDHA overexpression contributes to metabolic enhancement associated with significantly increased mitochondrial respiration as well as glycolysis in some of the cell lines leading to increased ATP production rate.As another approach to assess the impact of SDHA upregulation on cellular metabolism, we tested ovarian cancer dependence on nutrients essential for tumor growth. We deprived ovarian cancer cells of selected metabolic nutrients such as glucose or glutamine, or replaced glucose with galactose in culture medium. Glucose is required by cells to produce ATP via glycolysis, and to fuel TCA cycle with pyruvate. Replacing glucose with galactose forces cells to rely almost exclusively on mitochondrial OXPHOS for ATP production . GlutamiTo determine if SDHA overexpression redirects cellular metabolism in response to nutrient deprivation, we cultured selected ovarian cancer cell lines in low glucose, low glutamine or galactose medium  and assessed cellular respiration by the Seahorse XF Cell Mito Stress Test . We obseTo better understand cellular energetics in SDHA overexpressing ovarian cancer cells deprived of nutrients, we quantified ATP production rate. We observed that ovarian cancer cells showed substantial metabolic plasticity, which enabled the cells to switch between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions during experiment . Our datFurther, we analyzed a total ATP production rate in OVCAR3 cell lines in conditions with low glucose or low glutamine supply. Following glucose deprivation, OVCAR3 cells were capable to fully compensate for a loss in glycolytic ATP production by increasing their mitochondrial ATP production rate E. Such mCollectively, these findings indicate that SDHA overexpressing cell lines are not able to fully compensate for the loss of ATP production following glucose or glutamine deprivation, which results in a significant drop in a total ATP yield. In contrast, the corresponding SDHA-low cells demonstrated an improved metabolic capacity allowing them to better maintain a constant ATP production rate in nutrient deprived conditions. These data also suggest that SDHA overexpressing cells can be more sensitive to a deficiency in essential nutrients or cellular stress.We reasoned that SDHA overexpressing cells could be particularly vulnerable to drugs disrupting glucose and/or glutamine metabolism. To identify agents specifically targeting the SDHA overexpressing ovarian cancer cells, we utilized a custom compound library (from Seleckchem) composed of 64 anti-metabolic compounds . First, Lithospermum erythrorhizon plant) is a Chinese herbal medicine that has been known for its anti-inflammatory and anti-microbial activity [Next, we selected 7 the most potent anti-metabolic compounds and evaluated their efficacy in SDHA-high vs. SDHA-low cell lines. We observed that both shikonin and methotrexate significantly reduced viability of SDHA-high cell lines when compared with SDHA-low counterparts, however the shikonin was the most effective agent in specifically killing SDHA overexpressing cells B. Furtheactivity . More reactivity ,20. NextCollectively, we identified a highly potent compound shikonin that effectively kills SDHA overexpressing ovarian cancer cells. The SDHA overexpression strongly sensitized cancer cells to shikonin, which exhibited a profound anti-tumor efficacy superior that seen with traditional chemotherapy.The reprograming of cellular metabolism is an essential mechanism of tumorigenesis. The metabolic plasticity allows cancer cells to adapt to various unfavorable microenvironmental conditions and sustain uncontrolled cell proliferation, which promotes tumor progression and metastasis ,41. In tSuccinate dehydrogenase has been previously studied in the context of its deficiency in some rare disorders and malignancies ,15,16,17In the present study, our initial findings highlighted a potential importance of SDHA upregulation in ovarian cancer and set the stage for further more rigorous research. First, we performed an analysis of SDHA expression in a collection of healthy fallopian tubes and HGSOC PDX models, which showed that SDHA protein levels are significantly lower in fallopian tubes than in PDX tumors. Further, we observed that ovarian PDXs and established ovarian cancer cell lines exhibit a range of SDHA expressions. Importantly, the percentage (23.5%) of SDHA-high PDX tumors in our data set is consistent with the percentage (19%) of ovarian tumors harboring amplification and/or overexpression of SDHA in patients population (TGCA data set) . Our finTo evaluate the SDHA biological functions in ovarian cancer, we assessed the effect of SDHA overexpression on cell proliferation and in vivo tumor growth. The in vitro experiments revealed that SDHA upregulation is associated with a reduced cell proliferation in some cell lines, while in other cell lines the proliferation of cells is only marginally affected. In vivo data showed a tendency towards reduced tumor growth rate in mice bearing OVCAR3 tumor model. Our findings are in agreement with published studies. For instance, Xu et al., reported that the overexpression of SDHA in renal carcinoma cells inhibited cell proliferation in vitro and suppressed tumor growth in a nude mouse model in vivo . DiffereFurther, our work demonstrated that SDHA overexpression is associated with a generation of significantly more and larger cancer cell colonies in anchorage-independent conditions. It has been shown that aggressive and metastatic tumor cells are able to survive and rapidly propagate in the absence of anchorage to the extracellular matrix, while less tumorigenic or normal cells undergo growth inhibition and/or apoptosis (a process known as anoikis) . These dIn the present study, we set out to investigate the differences in bioenergetic profiles of ovarian cancer cell lines overexpressing SDHA vs. their respective SDHA-low counterparts. The cell lines showed a substantial diversity in their bioenergetic requirements, which was associated with the SDHA overexpression status. Our data consistently demonstrated that the cell lines with SDHA overexpression showed a significantly higher mitochondrial respiration, and tended to have higher maximal and reserve glycolytic capacity. This highly metabolically active phenotype of SDHA overexpressing cells was reflected by significantly increased total ATP yield. Variability in bioenergetic profiles and metabolic plasticity have been previously described in ovarian cancer and other tumor types by others ,32,48,49In our study, we also noted that all cell lines regardless of SDHA status preferentially used glycolysis pathway to fulfill their energy requirements as assessed by higher rates of ATP production from glycolysis than from OXPHOS, which is also in agreement with published data ,51,52. SIn different sets of experiments, we deprived ovarian cancer cells of glucose or glutamine to determine if SDHA overexpression redirects cellular metabolism in response to nutrient deficiency. The cells showed substantial metabolic plasticity switching between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions. We observed that glucose limitation significantly reduced ATP production from glycolysis that has been compensated with a higher ATP yield from OXPHOS, while glutamine deprivation increased glycolytic ATP yield suppressing ATP production via mitochondrial respiration. Such metabolic flexibility allows cells to become more resilient in variable conditions of tumor microenvironment ,9,32,53.In summary, our work provided novel insights into the role of SDHA upregulation in reprogramming of energy metabolism in ovarian cancer. We showed that SDHA overexpressing cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. While this phenotype may not drive a higher proliferation rate, it improves cells’ ability to survive anchorage-independent conditions. Importantly, we found that ovarian cancer cells with elevated SDHA are more vulnerable to deprivation of both glucose and glutamine, which is associated with a substantial reduction of ATP yield in those cells. Lastly, we implemented a drug screening strategy and identified anti-metabolic compound shikonin, which demonstrated a specific and potent efficacy against SDHA overexpressing ovarian cancer cells. Our future directions will be focused on pre-clinical testing of shikonin as a promising therapeutic approach for SDHA-amplified tumors. This work is a major step towards our long-term goal, to develop innovative ways to precisely target ovarian cancer-specific metabolism to improve treatment options for ovarian cancer patients.


Starter Lactic Acid Bacteria (LAB) are responsible for converting lactose to lactic acid during cheese manufacturing and, as a result, play a critical role in defining the attributes of the final product. There is great interest in isolating novel starter LAB strains to provide alternatives to existing industry cultures or to help enhance the quality and safety of cheeses traditionally made without starter cultures addition [1].The Fast-Slow Differential Agar (FSDA) medium was developed in 1984 and still remains the standard to rapidly differentiate fast and slow milk-coagulating lactic streptococci and thus avoid screening a large number of isolates for acid production capacity [2]. However, we found that FSDA was unable to selectively isolate fast acid-producing strains from young, traditional, starter-free Izmir Brined Tulum cheeses, due to the presence of a diverse microbiome including Non-Starter LAB and spoilage Gram-negative microbiota .•Nalidixic acid is an antibiotic that primarily inhibit Gram-negative bacteria [4].•Ascorbic acid and yeast extract stimulate the growth of lactic streptococci [5] and were added to complement skim milk in creating an environment favoring the growth of lactose-positive, casein peptides-utilizing LAB.•The pH indicator bromocresol purple enabled the chromogenic discrimination between LAB with different acid production capability.Here, we describe a modified FSDA (mFSDA) with increased selectivity and recovery efficiency towards lactic streptococci, which was successfully used to rapidly isolate potential starters from Tulum cheeses [1] and could similarly outperform FSDA in raw milk cheeses and other varieties containing high levels of “background” microbiota. The main differences between FSDA and mFSDA media consist in the presence of nalidixic acid, ascorbic acid and yeast extract in mFSDA. These targeted additions provide mFSDA with a two-prong selectivity that (I) suppresses unwanted microbiota, and (II) increases the recovery efficiency of lactic streptocci adept to using milk nutrients. Specifically:  Specifications tableThe composition of mFSDA medium is provided in For mFSDA bromocresol purple was chosen over litmus as it was reported to be equivalent to litmus by the developers of the FSDA medium Schleiferilactobacillus harbinensis, while most potential spoilage microorganisms were unable to grow on mFSDA except for Bacillus subtilis. Most of the LAB species tested also produced acid, except for some species normally associated with the Non-Starter LAB microbiota, such as Levilactobacillus brevis, Lentilactobacillus parabuchneri and Latilacobacillus curvatus.The mFSDA medium was initially validated using a bank of 27 Gram-positive and Gram-negative bacteria isolated from raw milks, dairy plants and cheeses during previous projects and stored in the Teagasc DPC culture collection . ResultsFollowing this successful validation, we tested the ability of mFSDA to isolate potential starter streptococci strains from young Izmir Brined Tulum cheeses. Due to the absence of starter addition during manufacturing, young samples of this traditional cheese variety can accumulate spoilage Gram-negative microbiota A key trait of a starter culture for cheese production is the ability to grow rapidly in milk and reduce the pH to ≤ 5.3 in 6 hours. On the other hand, non-starter LAB grow slowly in milk and do not cause such a pH reduction as they are generally lactose-negative and use peptides and free amino acids released from casein by the action of the starter LAB and residual chymosin in the cheese as their nitrogen source Streptococcus infantarius subsp. infantarius and Streptococcus macedonicus, were confirmed to be good acid producers when grown in 10% reconstituted skim milk.In agreement with this, results of the related study In conclusion, the newly developed mFSDA medium affords the same rapid and direct selection of fast acid-producing strains of lactic streptococci as the original FSDA medium while enhancing the recovery efficiency in environments containing background Gram-negative microbiota.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Eosinophilic esophagitis (EoE) is a complex, chronic, allergic disease that commonly presents as dysphagia in young adults. Co-occurring allergic or atopic disease, including food allergies and asthma are seen in approximately 70% of cases. Allergy to house dust mite (HDM) tropomyosin, Der p 10, and cross-reactivity to shrimp has been well described. We discuss a presentation of EoE in the setting of positive HDM skin prick testing that subsequently improved with dietary elimination of shrimp, that has never been described in the literature.To highlight an underlying mechanism in EoE and the importance of a multidisciplinary approach to this disease.A 45-year-old male with a medical history significant for ulcerative colitis  and asthma  was seen by his outpatient gastroenterologist following three weeks of new-onset dysphagia and subjective intermittent food bolus impaction. The patient was pre-emptively started on daily proton pump inhibitor prior to endoscopy, but discontinued this within less than two weeks as he felt like it induced loose bowel movements. Esophagogastroduodenoscopy (EGD) was performed and revealed proximal esophageal furrows. Histology of esophageal biopsies was compatible with EoE: distal esophagus >100 eosinophils/hpf with eosinophil degranulation, mid and proximal esophagus >25 eosinophils/hpf with eosinophil degranulation. The patient self-identified that his episodes of dysphagia and food bolus impaction were associated with shrimp ingestion, thus he eliminated shrimp from his diet.Dermatophagoides pteronyssinus and farina) but negative testing to shrimp, despite clinical improvement with dietary shrimp elimination. Thus his EoE was attributed to HDM cross-reactivity, specifically to the Der p 10 antigen. Follow-up EGD and biopsy to confirm endoscopic and histologic remission with shrimp elimination is scheduled in two months.Two-month clinical follow-up demonstrated symptomatic remission despite no other active treatment or additional food elimination. Consultation with an allergist demonstrated the patient had positive skin prick testing to HDM  shrimp, but often only demonstrate positive skin prick testing to HDM (with negative testing to shrimp). This case demonstrates a role for involvement of an allergist and skin prick testing in select cases of EoE, as this may result in a relatively simple food elimination and avoidance of further therapeutic interventions.NoneNone Declared


Prehospital airway devices are often classified as either basic or advanced, with this latter category including both supraglottic airway (SGA) devices and instruments designed to perform endotracheal intubation (ETI). Therefore, many authors analyze the impact of SGA and ETI devices jointly. There are however fundamental differences between these instruments. Indeed, adequate airway protection can only be achieved through ETI, and SGA devices all have relatively low leak pressures which might compromise both oxygenation and ventilation when lung compliance is decreased. In addition, there is increasing evidence that SGA devices reduce carotid blood flow in case of cardiac arrest. Nevertheless, SGA devices might be particularly useful in the prehospital setting where many providers are not experienced enough to safely perform ETI. Compared to basic airway management  devices, SGA devices enable better oxygenation, decrease the odds of aspiration, and allow for more reliable capnometric measurement by virtue of their enhanced airtightness. For all these reasons, we strongly believe that SGA devices should be categorized as “intermediate airway management devices” and be systematically analyzed separately from devices designed to perform ETI. Prehospital airway management devices are often classified as either basic or advanced. According to many recent prehospital studies, both supraglottic airway (SGA) devices and devices designed to perform endotracheal intubation (ETI) represent the advanced category and are therefore analyzed jointly ,2,3,4. IThere are fundamental differences between SGA and ETI devices. While mastering ETI requires considerable clinical expertise , even moIn addition, in studies differentiating ETI from SGA device insertion, clinical outcomes are often different between groups. For instance, a recent study reported the highest mortality and the lowest rate of good neurological performance after out-of-hospital cardiac arrest when SGA devices were used . The reaFurther supporting the separate categorization of SGA devices to explore cardiac arrest related outcomes, a recent simulation study unexpectedly discovered that chest compressions were significantly shallower when ventilation was performed when SGA devices were in place than when bag-valve mask devices were used . Should Even though we are of the opinion that systematically categorizing SGA devices separately from ETI and BVM  devices is scientifically sound and could help optimize prehospital care protocols, fellow authors and researchers may disagree with us for diverse reasons. Indeed, researchers working in systems where ETI capacities are always available may consider that analyzing SGA devices separately is not worthwhile. However, many prehospital providers are neither allowed nor trained to perform prehospital ETI, and SGA devices represent the next best option in such situations. In addition, other researchers might consider that almost all emergency prehospital providers should have been taught and allowed to use SGA devices by now. While we are convinced that enabling the vast majority of prehospital providers to use SGA devices is an important objective since these devices readily improve oxygenation and ventilation in many situations, certified paramedics are still not allowed to use such devices in certain regions of the world .We are aware that acknowledging a new category of airway management devices could be considered controversial since different opinions regarding airway management devices have been expressed in the literature, and some authors may even consider our position as provocative. Nevertheless, given the aforementioned differences and the impact they may have on clinical outcomes, we strongly believe that an intermediate airway management category incorporating all SGA devices should be acknowledged. By allowing the specific appraisal of the clinical impact of these devices, policy changes could subsequently be considered in certain settings where airway management resources are scarce.


Cognitive control decline is a major manifestation of brain aging that severely impairs the goal-directed abilities of older adults. Magnetic resonance imaging evidence suggests that cognitive control during aging is associated with altered activation in a range of brain regions, including the frontal, parietal, and occipital lobes. However, focusing on specific regions, while ignoring the structural and functional connectivity between regions, may impede an integrated understanding of cognitive control decline in older adults. Here, we discuss the role of aging-related changes in functional segregation, integration, and antagonism among large-scale networks. We highlight that disrupted spontaneous network organization, impaired information co-processing, and enhanced endogenous interference promote cognitive control declines during aging. Additionally, in older adults, severe damage to structural network can weaken functional connectivity and subsequently trigger cognitive control decline, whereas a relatively intact structural network ensures the compensation of functional connectivity to mitigate cognitive control impairment. Thus, we propose that age-related changes in functional networks may be influenced by structural networks in cognitive control in aging (CCA). This review provided an integrative framework to understand the cognitive control decline in aging by viewing the brain as a multimodal networked system. Over the past 20 years, the proportion of older adults in the population has expanded rapidly . AdvanceTo date, a major focus in neurocognitive aging research was linking cognitive control declines to specific regions . From thAccumulating evidence has suggested that CCA can arise from changes in connectivity among brain networks . NetworkMultiple large-scale networks facilitate specialized mental functioning for cognitive control . These nDecreased functional segregation occurs with aging . FunctioPreliminary evidence has suggested that decreased functional segregation of the TPN is associated with a decline in cognitive control with age. For example, in older adults, lower intra-connectivity within frontoparietal and attention network indicates worse cognitive control, and enhanced inter-connectivity between the frontoparietal and dorsal attention networks is associated with cognitive control decline . FunctioFunctional integration  reflects the integrated processing of information during tasks and usually manifests as enhanced functional connectivity . EnhanceFunctional integration among the frontoparietal network may be an important neural indicator of the cognitive control ability during aging. In older adults, functional connectivity between prefrontal and parietal cortex, i.e., within the frontoparietal network, positively predicts their performance during tasks requiring cognitive control . FurtherFunctional integration between frontoparietal network regions  and task-specific regions is associated with CCA (as illustrated in Finally, functional integration, as measured by network efficiency properties, declines with aging. Network integrative processes can be viewed as the communication efficiency measured by graph-theoretic properties . In addiCognitive control relies on functional antagonism between large-scale networks. Functional antagonism differs from functional segregation. Functional segregation usually refers to positive functional connectivity, where blood-oxygen dynamics between regions are predominantly positively correlated, whereas functional antagonism refers mainly to negative connectivity, where the blood oxygen level-dependent signals between paired regions are predominantly negatively correlated . FunctioDeclines in functional antagonism are important neurological indicators of the decreased cognitive control in older adults (as illustrated in Aging-related changes in the functional connectivity of large-scale networks are important contributors to CCA. Specifically, decreased functional segregation, integration, and antagonism are associated with worse behavioral performance measured by control-based tasks in older adults . DespiteAnatomically, a large number of isotropic axons are “bundled” together to form white matter fibers. These fibers form a structural network that ensures the transmission of electrical signals across brain regions . In healAge-related structural changes in the white matter involve both decreases in white matter volume and impairment of structural connections . Voxel-bBoth white matter loss and structural disconnection suggest a decrease in neural signaling capacity and are associated with decreased cognitive control . In oldeFunctional networks may serve as mediators of the cognitive control decline triggered by structural network damage. The impairment perspective proposes that damage to structural connections can weaken functional connectivity. Studies have shown that structural connections support functional connectivity in healthy older adults. For example, However, the damage perspective cannot explain some of the existing empirical results and may lead to a view of functional connectivity compensation (A relatively intact structural network may be a prerequisite for functional connectivity compensation, while severe lesions in the structural network can trigger reduced functional connectivity. When considering a network as a whole, a marked similarity between functional and structural networks can be observed . StructuStructural and functional networks show complex interactions affecting CCA. Because structural connections support and constrain functional connections, it could be concluded that structural connection damage triggers cognitive control decline by weakening functional connectivity. However, when the structural network is locally damaged but globally preserved, the effects on functional connectivity may be compensated through third-party structural pathways and may counteract the cognitive control decline associated with the structural damage. Functional compensation determined by preservation of the structural network should be considered in future explorations of network mechanisms underlying CCA.Aging-related changes in structural and functional connectivity among networks are involved in decreased CCA. However, to date, CCA-related network mechanisms have been established based on correlative evidence . In the Common and unique network mechanisms underlie cognitive control. Cognitive control can be divided into three core subcomponents: working memory, inhibitory control, and cognitive flexibility . All thrAging-related network mechanisms underlying the different subcomponents of cognitive control may be both shared and unique. Declines in functional connectivity within the frontoparietal network are associated with decreased CCA ; howeverpriori variable. In future, researchers should systematically collect multimodal imaging data, select targeted connections or networks, and construct mediating and moderating multivariate models to clarify how structural and functional networks interact and influence CCA.Multimodal network mechanisms for CCA are mostly theoretical, and empirical studies are rare. The impairment perspective suggests that CCA follows the pathway of “structural connectivity impairment → functional connectivity impairment → cognitive control decline.” However, the compensation view suggests that if the structural network is mostly preserved, the compensation of functional connectivity can be occurred through third-party structural pathways, as manifested by increased functional connectivity and cognitive control maintenance. When the structural network is severely disrupted, the functional network will be damaged and result in declines in cognitive control. Thus, structural and functional networks act together in a complex way in CCA, and the degree of structural network impairment may be an important a Notably, communication models and multilayer network analyses that emerge from network science would offer approaches to explore the structure–function coupling of brain networks . By formWhether changes in dynamic functional connectivity are involved in decreased CCA should be examined. Dynamic functional connectivity refers to the time-varying fluctuations of functional networks . CognitiCognitive control decline is a salient feature of aging. Abnormalities in the functional segregation, integration, and antagonism of functional networks suggest that disrupted spontaneous network organization, failed information co-processing, and increased endogenous interference in cognitive control are related to reduced CCA. Severe damage to the structural network can induce cognitive control decline by weakening functional connectivity. Nevertheless, a relatively intact structural network can ensure the compensation of functional connectivity, to delay the decline in CCA. Future research should introduce network neuroscience approaches and investigate the multimodal network mechanisms of aging-related cognitive control decline.HX: writing and revising the article, drafting, and proofreading references. QH and AC: reviewing and revising the manuscript and giving critical comments. All authors contributed to the article and approved the submitted version.


Arthropod bite mastitis is rarely encountered in imaging practices but can occur in all regions of the world. Diagnosis is often challenging as the offending agent is rarely identified. While most manifestations are self-limited, severe presentations can mimic malignant processes such as Paget’s disease and inflammatory breast cancer (IBC). This case demonstrates the diagnostic challenges sometimes encountered with arthropod bite mastitis as well as imaging findings both prior to and after interventions. While insect and arachnid bites occur worldwide, mastitis resulting from these arthropod bites remains a rare clinical entity with few case reports described -3. ArthrA 56-year-old woman presented with a three-month history of a right breast erythematous macular rash with scaling, which persisted despite the application of a topical antibiotic. The patient reported no antecedent trauma as well as no associated drainage, fever, or chills. During this time, she worked in a grocery store and began handling boxes of produce. At times, she noted occasional spiders and insects around the produce containers.Initial diagnostic mammography demonstrated an asymmetry with architectural distortion and skin thickening in the inferior right breast, with associated non-specific hypoechoic tissue on targeted ultrasound Figure . Punch bA short-term follow-up mammogram in four months demonstrated progressive skin thickening and an enlarging asymmetry in the inferior right breast, with a questionable underlying mass on targeted ultrasound Figure . The finAlthough clinical presentations are rare, arthropod bite mastitis can occur worldwide and should be considered in breast imaging workups ,4. In maNo specific diagnostic imaging criteria are available for arthropod bites, although superficial edema and inflammation are expected . DiagnosIf arthropod bite mastitis is expected, clinical follow-up and possible short-interval follow-up imaging (three to six months) may be suggested to ensure a benign clinical exam or resolution of imaging findings. Specific treatments depend upon the arthropod responsible for the bite, with pharmacologic and nonpharmacologic approaches providing relief . When clSevere presentations of arthropod bite mastitis can mimic breast malignancy, including Paget’s disease and inflammatory breast cancer. Diagnosis is often challenging, and a biopsy may be needed to exclude an underlying malignant process. Awareness of this entity and reliable clinical information such as symptom onset and duration are key to preventing unnecessary additional interventions.


Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for new therapeutics that otherwise have shown significant successes in disease control. Hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and is widely targeted in drug development. We found that resistance to the HGF-neutralizing antibody drug candidate rilotumumab in glioblastoma cells was acquired through HGF overproduction and misfolding, which led to stress-response signaling and redirected transport inside cells that sequestered rilotumumab and misfolded HGF from native HGF and activated Met receptor. Resistant cells were more malignant but retained their sensitivity to Met kinase inhibition and gained sensitivity to inhibition of stress signaling and cholesterol biosynthesis. Defining this rapidly acquired, multisystem scheme improves our understanding of drug resistance and suggests strategies for early detection and intervention.MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of  MGMT which encodes an alkyltransferase capable of repairing the DNA damage. The issue has become even more vexing with the development of highly selective agents such as those targeting the epidermal and hepatocyte growth factor  pathways. Acquired resistance to gefitinib or erlotinib in lung adenocarcinomas is a prevalent response to prolonged treatment and occurs through HGF pathway activation and other molecular mechanisms , often through increased expression of hanisms . Ant. AntMGMTHGF and MET genes are expressed in human glioma and medulloblastoma, where their increased relative abundance frequently correlates with tumor grade, tumor blood vessel density and poor prognosis . Quantitative PCR analysis showed that the mRNA transcript levels for HGF v1 and v3, the full-length variants, were more than 600- and 100-fold more abundant in the resistant cell line relative to the parental, respectively  and the most significant IPA “Molecular and Cellular Function” identified was “Cellular Growth and Proliferation” . Twenty-six IPA “Canonical Pathways” were identified as having significant overlap with the dataset by right-tailed Fisher’s Exact test and the Benjamini–Hochberg (B–H) multiple test correction , and group 6 pathways are consistent with a cellular origin of GBM. Phenotypic groups 1 and 2 however—stress signaling and immune-related pathways—suggested processes and pathways by which autocrine HGF/Met activation could evade contact with rilotumumab.P. pastoris) provide low yields of active protein unless they are specifically engineered to overexpress protein disulfide isomerase(s) to facilitate the correct disulfide bond pairing required for proper folding  or smaliewed in ,69,70,71HGF and MET gene amplification and HGF protein super-production; (2) downregulation of ER-resident disulfide isomerases contributing to significant HGF protein misfolding; (3) induction of ER stress-response signaling and intracellular HGF and Met protein retention; and (4) dramatically increased rilotumumab uptake and degradation through a shift to caveolar endocytosis and activation of antigen presentation pathways. Together, these changes provided intracellular seclusion of properly folded HGF and Met proteins from rilotumumab and maintained HGF/Met signaling dependence for cell growth and survival.Acquired drug resistance obstructs the effective treatment of many cancers and occurs through various mechanisms, often involving the elimination of drug from target cells or new defects in proto-oncogenes or tumor suppressors that revitalize essential growth and survival signaling pathways. Here we report a novel route to acquired resistance. In glioblastoma cells that require autocrine hepatocyte growth factor (HGF)/Met signaling for proliferation and survival, resistance to the HGF neutralizing monoclonal antibody rilotumumab was acquired through a complex interplay of several intracellular systems: (1) Unlike other acquired drug-resistance mechanisms, mutation of the gene encoding the drug target, loss of critical negative regulators downstream of the drug target, and/or activation of alternative mitogenic pathways parallel to the target were not observed. Despite the number and diversity of the subcellular systems involved, resistance developed rapidly in GBM cells in which HGF is an important oncogenic driver. Defining this mechanism also revealed targetable co-acquired dependencies for survival in resistance cells: cholesterol synthesis needed for caveolar uptake and ER-stress signaling as well as continued sensitivity to small-molecule Met tyrosine kinase inhibitors. These findings suggest strategies for the early detection of this form of resistance and for effective intervention.


The COVID-19 pandemic impacted predoctoral psychology training at the graduate, practicum, and internship levels including a greater reliance on telehealth and evolving learning needs. However its unique impact on geropsychology training has not been explored. The Building Bridges workgroup for predoctoral training faculty levels, we describe opportunities and barriers to address evolving geropsychology training needs during the pandemic as determined through working group discussion. Negative impacts to training identified include: decreased opportunities for 1) face-to-face patient care and 2) telehealth care due to disparities in telehealth access and utilization in older adults. Other impacts on the geropsychology pipeline include declining opportunities to see older adults at practicum sites. Conversely, increased media attention to the impact of COVID on older adults’ physical and mental health may lead to graduate students’ having greater interest in geriatric mental health and reinforcing a geropsychology career. Recommendations for training programs to address the long-term ramifications of the pandemic will be offered.


The continued demographic shifts in population aging are coupled with an increase in self-identified, LGBTQ+ individuals entering older age. While they share some common age-related experiences with non-LGBTQ+ individuals, they also face unique challenges as they age, including additional intersectional pressures beyond their sexual or gender identity. These challenges are exacerbated by pre-existing health inequities and heteronormative social support systems. Of particular concern is the ability to locate affirming and accessible social and health services. Gerontologists have a critical role in assisting older LGBTQ+ individuals in navigating complex social systems. To do so requires they have the appropriate education to develop the cultural humility needed to understand and assist these individuals. It necessitates the engagement of gerontology and geriatric education programs in educating future gerontologist professionals about LGBTQ+ older individuals. Critically, it requires the identification of appropriate instructors who are equipped to educate on LGBTQ+ aging topics.


Social support from family provided benefits for coping during the COVID-19 pandemic; however, not all older adults had access to family. The present study investigates how older adults without access to traditional family ties conceptualized their social relationships throughout the first two years of the pandemic. A subsample of eight older adults without direct access to traditional family ties were identified from a larger 5-wave interview study conducted between April 2020 and June 2022. Transcripts were holistically coded and three overarching themes emerged: constraints of place, redefining family, and feelings of isolation and closeness. The first theme addressed having family members living far away and uncertainty of when they would get to see them again. However, these distance barriers could be overcome through technology. The second theme illuminated that during the pandemic, those without access to traditional family ties redefined their social relationships by developing fictive kin from neighbors, colleagues, and friends. The third theme highlighted that some older adults felt they were lacking strong social networks and were concerned they had nobody to contact if they needed help, while others felt that despite limitations, their social relationships grew closer due to connection through alternative forms of communication (e.g. texting). Results from this study clarify how traditional family ties were challenged and strengthened during physical distancing for some older adults. These findings extend the literature on how fictive kin forms in older adulthood during temporary crises and suggests potential avenues for social connection for older adults lacking traditional family support.


Recent investigations of the mechanisms through which stress may impact cardiometabolic health point to the potential importance of cognitive tendencies  in this relationship. This study examined the associations between vigilance and stress coping with metabolic risk, and whether these associations varied by race and life course socioeconomic status (SES). Data come from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, a cohort of urban adults . Vigilance was measured by the MacArthur Reactive Responding subscale; stress coping was measured by the Brief Cope scale. Metabolic risk was operationalized by metabolic syndrome z-scores (MetS-Z). Linear mixed models were used to examine longitudinal associations between cognitive tendencies and MetS-Z; interaction terms were used to examine effect modification by race and life course SES. Black participants reported higher adaptive coping; participants experiencing persistent poverty or downward mobility reported higher vigilance and avoidant coping and lower adaptive coping. Overall, vigilance was not associated with metabolic risk. Avoidant and adaptive coping were inversely associated with baseline MetS-Z and further varied by sociodemographic factors. Higher adaptive coping was associated with lower MetS-Z among White adults, while higher avoidant coping was associated with lower MetS-Z among Black adults. Lower stress coping were associated with higher MetS-Z among White participants with low lifecourse SES or downward socioeconomic mobility. In sum, stress coping may modulate the stress-health relationship, but these associations must be interpreted within the intersection of contextual factors.


Enterobacterales (CRE) presents a major threat to public health. CRE employ two molecular mechanisms to evade carbapenems: 1) expression carbapenemases (CPases), which efficiently hydrolyze carbapenems or 2) disruption of porins, which reduces carbapenem influx to levels that can be hydrolyzed by certain beta-lactamases. Diagnosing mechanisms underlying carbapenem resistance is important for infection control and to administer appropriate treatments.The global spread of carbapenem-resistant Enterobacterales isolated from hospitals in Massachusetts and California using broth microdilution assays at 14 inocula spanning four orders of magnitude. They represented 30 isolates encoding CPases and intact porins, 46 isolates with disruptions in one or both of the porins responsible for carbapenem influx (OmpC and OmpF), 25 encoding CPases with disrupted porins, and two controls encoding intact porins and no CPases.We measured Meropenem and Ertapenem minimum inhibitory concentrations (MICs) for 103 clinical We observed that the two mechanisms result in distinct profiles; first the carbapenem MICs of CPase-encoding strains show a strong inoculum dependence , whereas the MICs of porin deficient strains remain largely constant at all inocula . The synergistic action of these two mechanisms leads to high-level resistance that we termed “hyper-CRE” . Together these factors explain the level of resistance in nearly all our CRE isolates. To validate the hyper-CRE phenotype, we successfully employed CRISPR-based gene editing to show that knocking out the major porin in CPase-producing strains elevates their carbapenem resistance to hyper-CRE levels.in vitro AST assays but are truly resistant in vivo.We also determined 18% of our isolates changed susceptibility classification within the Clinical Laboratory and Standards Institute (CLSI) recommended inoculum range. This is worrisome for the treatment of infections with strains that are deemed susceptible via Overall, our approach has demonstrated that measuring MICs at different inoculum can yield crucial diagnostic information about mechanisms of resistance which has important implications for patient care, infection control, and surveillance of emerging CPases.All Authors: No reported disclosures.


A growing body of literature suggests that inclusion of ultra-processed foods (UPFs) in the diet may be associated with various non-communicable diseases, including obesity, cardiometabolic diseases, and increased mortality. However, one of the most underrated research topics is represented by the potential role of diet for mental disorders. The aim of this study was to explore whether there was an association between UPF consumption and mental health outcomes in a cohort of southern Italian individuals.Demographic and dietary data from 1572 adults living in southern Italy was collected. Food items were categorized by the level of processing according to the NOVA classification. Multivariate logistic regressions were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between UPF intake and mental health outcomes, including sleep quality and depressive symptoms.Individuals in the highest quintile of UPF intake were more likely to have low sleep quality compared to those with the least intake . Among the main component of sleep quality, high UPF intake was associated with sleep latency and efficacy individually. No apparent associations were found between UPF intake and depressive symptoms. However, when considering different age groups, younger individuals (age <40 y) consuming more UPF were more likely to have depressive symptoms than low consumers .These findings show a potential association between UPF consumption and mental health outcomes. Further studies are needed to understand whether the retrieved relation depends on alteration of the physiological feeding patterns leading to food-anticipatory and binge-type behaviors or on nutritional  and non-nutritional factors  triggering pro-inflammatory pathways.• Ultra-processed food consumption is associated with worse sleep quality and depressive symptoms in Italian adults.• The detrimental associations between ultra-processed food consumption and depressive symptoms seem stronger among younger individuals.


We conducted participatory design research for long term care (LTC) socially assistive robotic activities comprised of social, cognitive and physical components and enhanced human-robot (HRI) and human-human interactions (HHI). Repeated sessions were conducted with 10 geriatric experts  and 12 LTC residents (ages 70–92). Two robots, animal and humanoid, were used in combination with virtual reality. Four collaborative activities for paired older adults were designed and evaluated: playing drums to music, completing paintings, a fishing game, and training a dog with simple commands. Within each activity, three levels of difficulty were designed. Stakeholder feedback was obtained through observations and interviews. Numerous modifications were made following each session that addressed hardware, software and activity issues. Modifications were necessary both for the HRI and HHI aspects of the activity. Our experience demonstrates the necessity for participatory design in the deployment of technology for LTC settings.


The Age-Friendly University (AFU) initiative aims to increase the participation of age-diverse older adults in higher education communities. The present study investigated age-friendly practices across 23 institutions in the United States. The ICCS Inventory , which identifies 192 potential age-friendly campus practices was completed by administrators representing major campus units. A heat map was used to graphically represent age-friendly practices and identify where universities differed in the presence of those practices. Heat map findings indicated campuses are low in some auxiliary services that assist retired faculty and staff. However, campuses consistently gave retired faculty and staff access to university library services. Campuses also had limited age-friendly teaching and learning services. None of the campuses reported having resources to help faculty deliver teaching materials in formats specifically geared toward older learners. In addition, none of the campuses reported having teaching and learning staff visiting campus departments to provide resources for older learners, and very few campuses offered courses that focused on aging and age diversity issues. Common age-friendly practices were seen with respect to providing instructional technology support for faculty/staff/students and community partnerships for intergenerational activities. Physical environment and personnel evidenced the most frequent age-friendly practices likely because they are mandated by the ADA . Overall, the present study highlighted the areas where college campuses are most age inclusive, while also revealing areas for improvement in age inclusive practices.


Markers of functional aging can be used to track biological aging longitudinally and how it changes in response to the environment, e.g., drugs. We aimed to investigate how different drug classes may alter functional aging trajectories using data from the National E-infrastructure of Aging Research (NEAR) in Sweden. Data were harmonized across several longitudinal cohorts of aging for general cognitive performance, grip strength, walking speed, sensory ability , lung function and assessment of frailty using the accumulation deficit model known as the frailty index. Selected drug classes were lipid lowering, glucose lowering and blood pressure lowering medications that are commonly used in old adults. Preliminary analysis using data from one longitudinal cohort shows that using glucose lowering drugs was associated with lower frailty. Additional analyses are ongoing to increase sample sizes. We anticipate that several drug classes may be important for changing functional aging trajectories in late life.