There is a growing consensus on brain networks that it is not immutable but rather a dynamic complex system for adapting environment. The neuroimaging research studying how brain regions work collaboratively with dynamic methods had demonstrated its effectiveness in revealing the neural mechanisms of schizophrenia.To investigate altered dynamic brain functional topology in first-episode untreated schizophrenia patients (SZs) and establish classification models to find objective brain imaging biomarkers.Resting-state-functional magnetic resonance data for SZs and matched healthy controls were obtained(Table1).Power-264-template was used to extract nodes and sliding-window approach was carried out to establish functional connectivity matrices. Functional topology was assessed by eigenvector centrality(EC) and node efficiency and its time-fluctuating was evaluated with coefficient of variation(CV). Group differences of dynamic topology and correlation analysis between Positive and Negative Syndrome Scale(PANSS) scores and topology indices showing group differences, which also were used in establishing classification models, was examed.The CV of node efficiency in angular and paracingulate gyrus was larger in SZs. There are 13 nodes assigned into several brain networks displaying altered CV of EC between groups. Fluctuation of EC of the node in DMN, which was lower in SZs, showed negative correlation with PANSS total scores. Dynamic functional topology of above nodes was used to train classification models and demonstrated 80% and 71% accuracy for support vector classification(SVC) and random forest(RF), respectively.Dynamic functional topology illustrated a capability in identifying SZs. Aberrated dynamics of DMN relevant to severity of patient’s symptoms could reveal the reason why it contributed to classification.No significant relationships.


Left ventricular rupture following prosthetic mitral valve replacement might be avoided by valve-sparing techniques and vigilance at the time of debridement to maintain or support annular integrity.See Article page 48.,DavidAlthough performing prosthetic MVR is not usual, few surgeons have had the misfortune of having to deal with LV rupture. Bright red blood emanating from the posterior pericardium upon separation from cardiopulmonary bypass following MVR is universally accompanied by a sinking feeling in the operator. Should an ill-prepared surgeon attempt lifting the heart to locate the bleeding source in this setting, the maneuver may prove fatal. As outlined by David,,Predispositions to this complication include female patients, a small LV cavity, advanced age, severe mitral annular calcification, and implantation of higher-profile bioprosthetic valves. Vigilance and patch correction at the time of annular debridement may avoid type 1 LV disruption, whereas avoiding deep debridement involving the papillary muscles can mitigate type 2 LV disruption. Posterior leaflet and total leaflet sparing MVR operations have nearly eliminated this complication.Greek mythological reference to Achilles' heel symbolizes that despite overall strength, a focal vulnerability may lead to downfall. Surgeons are well versed in the reproducible techniques of prosthetic MVR. Valve-sparing methods and adaptive strategies to address mitral annular calcification are the established necessary standards to avoid this potential vulnerability and circumvent this pitfall. Vigilance can often save patients from this often fatal problem.


The Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act (PL115-406) supports public health agencies to develop a uniform dementia infrastructure across the US. Applying a robust public health approach to ADRD that emphasizes data driven decision-making and action along with primary, secondary, and tertiary prevention strategies  for persons living with dementia and their caregivers. Recipients of the BOLD Public Health Programs funds are expanding jurisdiction Dementia coalitions, updating, or creating Dementia Strategic Plans, and implementing strategies from those plans that address a wide variety of life-course strategies for brain health and dementia, including risk reduction. This presentation will explain how risk reduction is integrated and provide examples of several activities being planned and implemented by recipients.


Ectodermal dysplasias (ED) are inherited disorders involving congenital abnormalities of different ectodermal structures, the most prominent presentation being adontia/hypodontiaIn this article, we present a brief overview of several pediatric cases of ED with a short review of the odontological manifestations.We report several cases of children consulting in the pediatric department for abnormal teeth, with or without systemic manifestations.The clinical examination of these patients revealed insufficient and abnormal dentition, with rare beveled teeth and thin and rare hair, as well as eyelashes and eyebrows.Also, parents reported episodes of hyperthermia without sweating from an early age.Dental radiography confirmed the diagnosis of ectodermal dysplasia.Ectodermal dysplasias (EDs) are a group of various inherited disorders involving abnormal congenital development of at least two ectodermal structures . The management of these rare disabling conditions is still mainly symptomatic. The traditional removable prosthesis can be an option to replace missing teeth. However, implants provide the best long-term results and prognosis. In particular, dental implants are commonly used in oral reconstruction of ED patients, but long-term data on bone augmentation and bone resorption, aesthetic outcomes, and implant success are needed.in utero.EDs are a myriad of heterogeneous conditions encompassing several inherited embryopathies affecting teeth and other ectoderm-derived structures Diagnosis is essentially clinical, confirmed by radiology and genetics which can specify the causal mutation; treatment is mainly conservative.


This presentation will review the current state of knowledge about severe maternal perinatal mental illness. Severe disorders are associated with a higher prevalence of somatic difficulties during pregnancy, poorer quality of pregnancy follow-up and potential impairment of infant care. These children are therefore very vulnerable and require specific care. We will present how graduated care coordinated and above all integrated between psychiatry, obstetrics, neonatal pediatrics and child protection services allows for early and effective preventive interventions, both for the child’s development and maternal mental health. The concept of shared parenting will be particularly developed.No significant relationships.


Editorial on the Research TopicDevelopmental origins of health and disease: Impact of preterm birthin utero environment that precipitates the early birth. Further, preterm birth has been associated with impaired structural and function development of organ systems in the offspring, thus making preterm birth a unique predisposing factor for adult disease  scores, but late preterm birth mothers had even higher depressive symptoms; both of which may affect the care provided to their respective infants.” Both Motte-Signoret et al. and Gonzales-Garcia et al. studied small for gestational age or intrauterine growth restricted (IUGR) infants. Motte-Signoret measured growth factor (GF), insulin growth factor 1 (IGF1), and insulin resistance in small for gestational age (SGA) infants. SGA infants demonstrated resistance to GF and IGF1 with insulin resistance. These findings could explain initial defects in early catch-up growth, risks for later catch-up growth, and higher prevalence of metabolic syndrome in later life. Gonzales-Garcia compared the Fenton 2013 growth charts to those from the International Fetal and Newborn Growth Consortium for the 21st Century (Intergrowth 21st) Project (IW-21) for assessing to intra-(IUGR) and extrauterine (EUGR) growth restriction in very low birthweight infants. There was concordance between the charts for IUGR growth trajectories but not for EUGR infants. The dynamic IW-21 was more restrictive but better predicted morbidities in EUGR infants.Reports on the negative effects of preterm birth included identifying predictors of severe necrotizing enterocolitis (NEC) and impaired neurodevelopmental outcomes and indicated that early identification of risk factors might ultimately lead to improved outcomes. Lin et al. sought to identify predictive indicators of necrotizing enterocolitis (NEC) by comparing biomarkers between NEC with portal venous gas (PVG) and NEC without PVG. C-reactive protein (CRP), fibrinogen degradation product, and blood glucose demonstrated predictive value for NEC-PVG. Current outcomes of the Neuroprem 2 cohort study were reported by Lugli et al. Out of 502 very preterm infants 9.6% had severe disability and 5.4% had cerebral palsy. Gestational age and periventricular hemorrhage were most highly associated with severe disability. Along these same lines, Wibowo et al. measured bone mineral content in newborns and found it lower in underdeveloped countries, higher in males, and negatively correlated with maternal cigarette usage. Hole et al. utilized a preterm piglet model to study early motor development. Preterm piglets took shorter steps than term piglets in early stages of walking but rapidly adapted with no differences within 3 days. Overall conclusions from the combined studies were that early interventions are needed to prevent later delays.Khasawneh et al. retrospectively analyzed determinates of late hospital discharge. The majority of all preterm births analyzed were late preterm infants. While several parameters such as gestational age and maternal and neonatal morbidities were correlated with length of stay , there was no correlation between length of stay after birth and later readmission.In summary, growth restriction and small birth weight can have permanent consequences on the metabolic health of the infant. Furthermore, the morbidities associated with preterm birth such as NEC, and motor and neurodevelopmental disabilities are likely to contribute to deficits in the quality of life once these infants reach adulthood. Prematurity and SGA should be considered overall risk factors for adult health and quality of life.


Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women  from the Women’s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership . Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect  were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia . The odds of being classified as this high-dementia risk group were increased among women with more (per SD) global small vessel ischemic disease , deep white matter SVID , and smaller parahippocampal volumes . For negative affect, with minimal stable negative affect as referent, women with smaller hippocampal volumes were more likely to be classified as having moderate decreasing negative affect  while emerging negative affect was associated with higher dementia risk . These findings highlight the importance of changes in affect in later-life with dementia risk and potential underlying role of cerebrovascular disease and medial temporal lobe structures.


Adenoviruses are commonly used as efficient high-capacity vectors and excellent gene delivery vehicles. Their applications range from basic molecular research to gene therapy and recombinant viral vector vaccines. Adenoviral vectors are currently used in regenerative and cancer therapies, and as first-generation COVID-19 vaccines. Despite their widespread use and constant progress, various challenges and safety concerns still limit the application of adenoviral vectors to their fullest potential. Our Special Issue, “New Aspects of Adenoviral Vaccine Vectors and Adenoviral Gene Therapy”, presents five excellent original research articles and reviews on adenoviral vector development, recent trends in adenovirus-mediated oncolytic therapies, and lessons learned from current large-scale adenoviral vector vaccination programs.An in-depth review article by Erwan Sallard and colleagues provides the latest insights into adenoviral vector design and reiterates lessons learned from adenovirus-based COVID-19 vaccines [A research article by Xiang Du and colleagues summarizes an in vivo proof of concept for a replication-competent adenovirus vector vaccine against a morbillivirus of veterinary importance . They shNora Bahlmann and colleagues contribute new data on improved adenovirus vectors for oncolytic and gene therapies . Their rA thorough review by Wen-Chien Wang and colleagues  recapituPaola Blanchette and Jose Teodoro comprehensively review the characteristics of oncolytic adenoviruses that are currently undergoing clinical trials for cancer therapy . Their oThis collection of articles provides valuable new insights into various properties of adenoviral vectors in vaccine and gene therapy settings—a topic that has been studied for decades but is more relevant than ever, as there have never been so many individuals injected with a recombinant adenovirus vector.


Communication is fundamental for dementia care and identifying evidence for strategies that facilitate or impede communication is needed. We analyzed 221 videos from a randomized controlled trial of a family caregiver telehealth intervention (FamTechCare) using Noldus second-by-second behavioral coding of communication behaviors and breakdowns in interactions between 53 caregiver-person with dementia dyads. Coded data from 3,642 30-second observations were first analyzed using penalized regression for feature selection  to identify strategies most important for predicting prevention and successful repair of communication breakdown. Bayesian mixed modeling was then used to identify communication strategies associated with successful versus unsuccessful prevention and repair of communication breakdown taking into account of the dyadic structure of our data. Results showed that given our data, communication breakdown was associated with caregivers changing topic , ignoring , making commands  and taking over the task . Successful repair of breakdown was associated with caregivers verbalizing understanding , tag questions, , and silence  while ignoring and changing topic were associated with unsuccessful repair . These results provide evidence for development and testing of evidence-based communication strategy training for family caregivers of persons with dementia. Future analyses will identify effects of dementia stage, diagnosis, and dyad characteristics on associations.


Mycobacterium tuberculosis DNA present in their stool samples, which can augment current diagnostic gaps. Optimizing extraction of DNA from stool for analysis via sequencing technologies is a paramount initial step to ensure accuracy of downstream sequencing applications.Next generation sequencing (NGS) is quickly coming to the forefront of diagnostic tools to provide efficient, highly informative information from patient samples. Recently, it was established that patients with pulmonary Tuberculosis (TB) have Mycobacterium bovis derived from BCG were used as a model for Mtb. Human stool samples were spiked with varying known concentrations of BCG and extracted with four different DNA extraction kits . Each sample was subjected to quantitative polymerase chain reaction using designed primers and probes specific for identifying Mtb infection from stool. The samples underwent further analysis to assess overall DNA yield (Qubit fluorometer), DNA fragment length (Agilent tape measure), and DNA purity (Nanodrop spectrophotometer).Attenuated strains of Overall, the Fast DNA Spin Kit for Soil extraction kit showed the most optimal results. DNA isolated via this method showed the lowest cycle thresholds of Mtb amplification, indicating the most preserved amount of BCG specific DNA. In addition, this method showed the highest overall DNA yield and highest proportion of long DNA fragment lengths. Fluorometric analysis showed significant contamination in the 230 nm wavelength range, which was amended with an additional AMPure bead cleanup step.Quantiative PCR of Spiked BCGQuantitative PCR Cycle Threshold Values by Different DNA Extraction KitsThe MPFast Soil Extraction kit, when compared to three other DNA extraction kits, performed the best on stool samples for isolating BCG DNA. Overall DNA yield, DNA length, and amount of specific BCG DNA were best optimized with this method and provided the best samples for sequencing analysis. This critical step is the first of many to realize the promise of stool-based NGS.DNA QuantityQuantity of Total DNA by Different DNA Extraction KitsSpectrophotometric AnalysisAnalysis of Absorption of Extracted DNA by Different DNA Extraction KitsSpectrophotometric ResultsSpectrophotometry Results of DNA Samples Extracted by Different DNA Extraction KitsLennard A. Meiwes, n/a, German Center for Infection Research (DZIF): Grant/Research Support.


Inner strength is a person’s internal process of moving through challenging circumstances, such as receiving a diagnosis of Mild Cognitive Impairment (MCI). This study describes experiences of inner strength using qualitative methodologies to identify themes within semi-structured dyadic and individual interviews with persons diagnosed with MCI within 12 months at a Memory Center and their care partners. We analyzed data in NVivo using reflexive thematic analysis methods. Trustworthiness was maintained through vetted interview guides, verbatim transcription, field notes, peer group analysis, and audit trails. One overarching theme and three subthemes explained inner strength. An overarching theme, Finding Ways to Live with It, described how participants live within the circumstances of MCI. Three subthemes were Defining Strength by Recalling the Past, Seeking Relief and Dwelling in It, and Finding Purpose & Meaning. Implications include supporting inner strength at the time of MCI diagnosis through reminiscence therapy and meaning making interventions.


There is growing interest in whether linked administrative data have the potential to aid analyses subject to missing data in cohort studies. We aimed to identify predictors of cohort non-response in linked administrative data and examine whether inclusion of these variables in principled methods for missing data handling can help restore sample representativeness.Using linked 1958 National Child Development Study (NCDS) and Hospital Episode Statistics (HES) data, we applied a multi-stage data-driven approach to identify HES variable which are predictive of non-response at the age 55 sweep of NCDS. We then included these variables as auxiliary variables in multiple imputation (MI) analyses to see if they helped restore sample representativeness in terms of early life variables which were essentially fully observed in NCDS  and relative to external population data .We took as our starting point 57 variables derived from HES data based on the presence or number of different types of appointments/admissions, diagnostic codes and treatment codes. After application of our multi-stage data-driven approach we identified five HES variables that were predictive of non-response at age 55 in NCDS. For example, cohort members who had been treated for adult mental illness were almost 3 times as likely to be non-respondents . Inclusion of these variables in MI analyses did help restore sample representativeness. However, there was no additional gain in sample representativeness relative to analyses using only previously identified survey predictors of non-response (i.e. NCDS rather than HES variables).In our applications, inclusion of HES predictors of NCDS non-response in analyses did not improve sample representativeness beyond that possible using survey variables alone. Whilst this finding may not extend to other analyses or NCDS sweeps, it highlights the utility of survey variables in handling non-response.


The Art of WarRecent technological advances have expanded our understanding of how artificial stimulation interacts with the living nervous system . Song and Martin found that cathodal tsDCS can selectively target voltage-dependent calcium channels to modulate motoneuron activity, informing therapeutic treatment strategies to achieve rehabilitation goals after injury; in particular, to increase muscle force.Significant research efforts have focused largely on developing non-invasive or minimally invasive stimulation techniques  in discriminating the MI condition from rest. Moreover, they showed that st-SES influences functional connectivity of the fronto-parietal network, but through different frequency bands for different subjects. These findings can potentially help to optimize guidance strategies to adapt to different types of MI-BCI users.In addition, motor imaginary (MI)-based brain-computer interface (BCI) must overcome multiple issues to be commercially usable, especially related to signal quality and subject-variation  for severe treatment-resistant depression. Steele et al. proposed a fronto-medial ECT electrode placement that would maximize the EF in specific sagittal brain regions, whilst minimizing EF in sub-regions of the bilateral hippocampi. Such outcomes suggest electrode location can significantly reduce cognitive and non-cognitive side-effects.An optimal implantation region improves not only stimulation performance but also the long-term stability of implantable microelectrodes, as well as reducing side effects  features and joint angles as inputs. A similar idea has been used historically in other neuromodulation fields since various stimulation parameters have been shown to evoke distinct neurological and physiological responses. Conversely, elicited physiological effects, both for targeted and untargeted neurons, can guide stimulus parameter tuning for many neural systems, including the brain  et al. have proposed a new biophysical model of myelin ultra-structures by simulating cytoplasmic channels in the myelin sheath as a low-impedance route, while previous models approximate the myelin sheath as an insulation layer  et al. further investigated how cytoplasmic channels affect EF across the myelin sheaths, concluding that the externally applied EF can control myelin growth. These new findings indicate the possibility of using electrical modulation to treat degenerative neural diseases. Neurodegenerative progression can affect the neuroprosthetic performance  using a biophysically detailed computational model of the human cochlea (Bai et al., Electrical stimulation performance cannot be significantly improved by only optimizing the device in isolation without considering the biophysical complexity of the target nerve system (Abbasi and Rizzo, The Chinese characters shown in the Editorial refer to the origin of each subtitle in the ancient literature The Art of War by Sun Tzu.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Adequate reproductive and maternal healthcare services utilization are significant in reducing maternal deaths, however, the prevalence rate of contraceptive use remains low, with inadequate maternal health services utilization among rural women in Nigeria. This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services utilization among rural women in Nigeria.The study analyzed data from a weighted sample of 13,151 currently married and cohabiting rural women. Descriptive and analytical statistics including multivariate binary logistic regression were conducted using Stata software.An overwhelming majority of rural women (90.8%) have not used modern contraceptive methods, with poor utilization of maternal health services. About 25% who delivered at home received skilled postnatal checks during the first 2 days after childbirth. Household poverty-wealth significantly reduced the likelihood of using modern contraceptives , having at least four ANC visits , delivering in a health facility  and receiving a skilled postnatal check . Women's decision-making autonomy regarding their healthcare significantly increased the use of modern contraceptives and the number of ANC visits, while women's autonomy on how their earnings are spent positively influenced the use of maternal healthcare services.In conclusion, the use of reproductive and maternal health services among rural women was associated with household poverty-wealth and decision-making autonomy. Government should formulate more pragmatic policies that will create awareness and promote universal access to reproductive and maternal healthcare services. In the context of global health priority, the levels of utilization of reproductive and maternal health services are parts of the indicators in measuring the level of healthcare performance, delivery system and developmental indices . The useMaternal healthcare including optimal ANC visits, delivery in a health facility and skilled postnatal check after delivery are significant mediations required during pregnancy and after childbirth for positive maternal and child health outcomes . AlthougIn sub-Saharan Africa, which Nigeria is part of, previous studies have shown the existence of urban-rural disparity in the use of maternal and reproductive health services by demonstrating that urban women tend to use modern contraceptives and maternal health services compared to rural women –14. NotwThis study examined household poverty-wealth and decision-making autonomy as predictors of reproductive and maternal health services utilization among rural women in Nigeria. The outcome is expected to provide up-to-date information, relevant policy and programmatic recommendations towards achieving sustainable development goals targets of universal access to quality reproductive and maternal health services; and reducing maternal and child deaths.The study utilized data obtained from the 2018 Nigeria Demographic and Health Survey (NDHS). The survey is a cross-sectional study and data were generated using standardized interviewer-administered questionnaires from a nationally representative sample of women aged –49 on soThe outcome variables selected for this study were based on empirical evidence which includes; 1) the use of contraceptive methods, 2) the number of ANC visits, 3) facility delivery services and 4) the postnatal check provider. Information on these outcome variables as generated from the 2018 NDHS was re-categorized from their original frequency ranges in the dataset. Therefore, women who used a modern contraceptive method, had at least four ANC visits during their most recent pregnancy, delivered in a public or private hospital and skilled postnatal check of a mother during the first 2 days after childbirth/before discharge from a doctor, nurse/midwife or auxiliary nurse/midwife were categorized as ‘1’ and ‘0’ if otherwise.The main explanatory variables in this study are household poverty-wealth and women's decision-making measures including the following three subjects: 1) decision on respondent's healthcare, 2) decision on large household purchases, and 3) decision on how to spend respondent's earnings. Therefore, women who made independent decisions on any of the three subjects represent decision-making autonomy and may influence seeking healthcare for themselves . In thisp<0.05 and measures of association were expressed as odds ratio with 95% confidence intervals.Data analysis was conducted with Stata software (version 15) at univariate, bivariate and multivariate levels. The dataset was carefully checked for missing values which were excluded and weighted with the appropriate sampling weights as per the Demographic and Health Survey sampling scheme. At the bivariate level, unadjusted logistic regression as shown in Description of the study population: The weighted descriptive statistics of the women as presented in Reproductive and maternal healthcare services utilization: Unadjusted and bivariate analysis: The unadjusted and bivariate results as presented in p<0.05. However, except for employment status and health insurance coverage, all the main explanatory variables and other covariates are significantly associated with receiving postnatal care from a skilled provider during the first 2 days after childbirth at p<0.05.Adjusted multivariate analysis of the utilization of reproductive and maternal healthcare services by explanatory variables: The adjusted logistic regression analysis results presented in This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services among rural women in Nigeria. The findings of this study revealed that despite the efforts in encouraging the use of modern contraceptive methods, the prevalence of modern contraceptives among rural women is still alarmingly low corroborating different studies in Congo  and EthiThe findings further revealed that rural women found in poor households were less likely to use modern contraceptive methods relative to those in rich households. This corroborates previous studies in sub-Saharan Africa including Nigeria that the poverty-wealth dimension in rural areas is a big factor contributing to the lack of modern contraceptive use –31. AlsoThis study showed that rural women's decision-making autonomy regarding their healthcare is a significant predictor of using modern contraceptive methods and having at least four ANC visits during pregnancy. The findings corroborate previous studies that women who can make independent decisions on their reproductive health were more likely than those whose husbands solely made such decisions to use modern contraceptives , 35 and The findings of this study further confirmed an observation that younger women were less likely to use modern contraceptives compared to their older counterparts . PlausibIn conclusion, this study found that the prevalence of modern contraceptives is still alarmingly low, while optimal ANC visits during pregnancy and delivery in health facilities are poorly utilized among rural women. Some rural women who delivered at home subsequently sought skilled medical attention from health facilities. Generally, reproductive and maternal health services utilization were negatively influenced by household poverty-wealth. Women's decision-making autonomy regarding their healthcare and earnings are significant predictors of reproductive and maternal health services utilization. There is a need for some unified skilled postnatal home-visit services outside health facilities through linkages with healthcare providers. Also, the government should formulate more pragmatic policies that will create awareness, educate and promote adequate reproductive and maternal healthcare services utilization among disadvantaged women.The study has some limitations including the use of secondary data from a cross-sectional study which restricts study variables. As a result, the cause-effect association between the explanatory and outcome variables is rather temporary and may not be ascertained. However, the findings are essential for the formulation of more pragmatic policies geared toward achieving universal access to reproductive and maternal healthcare services.


Previous research has demonstrated that self-concealment of sexual orientation may negatively affect the wellbeing of lesbian, gay, and bisexual (LGB) adults . Additionally, studies have indicated that internalized homophobia significantly predicts depressive symptoms in LGB older adults . The present study examined how internalized homophobia may mediate the predictive relationship between self-concealment on depression symptoms in LGB older adults. As part of a larger study, participants (Nf301) responded to several questions and measures including the Sexual Orientation Self-Concealment Scale, The Internalized Homophobia Scale, and the Center for Epidemiological Studies Depression Scale. Using the Baron and Kenny’s Method for Mediation (1986), the data analysis indicated that internalized homophobia fully mediates the relationship between self-concealment and depression severity (ps < .05). These results suggest that older adults who self-conceal their sexual orientation may experience an increase in depressive symptoms because of internalized homophobias. These findings may help clinicians better understand the mechanisms contributing to the high rates of depressive symptoms within the older LGB population. Furthermore, the findings suggest that cognitive restructuring of thoughts related to internalized homophobia and self-concealment may improve depressive severity in older LGB adults.


Molecular Cancer, Wang and his colleagues have now placed seven types of tumors in a unified analytic framework [Circular RNAs (circRNAs) are a subgroup of single-stranded endogenous RNAs which exert differential expression pattern between normal and cancerous tissues and function as important regulators in cancer initiation and progression. However, comprehensive characterization of circRNA landscape across cancer types is still lacking. In a recent article published in ramework , all wit, demonstrating circLIFR may serve as a therapeutical target in metastatic cancer. Consistently, the RNA-seq results suggested the ability of circLIFR to alter the expression pattern of some metastasis-related genes involved in cell adhesion and epithelial-mesenchymal transition (EMT). Collectively, this study by Wang et al. certainly illustrates the comprehensive circRNA profiles in multiple solid tumors and highlights the potential of circRNAs as important diagnostic tools or therapeutic targets.Through rRNA depleted transcriptome sequencing, the authors identified a total of 59,056 circRNAs, the majority of which were lowly expressed, while a subset of circRNAs exhibited much higher abundance than their cognate linear transcripts, indicating their biological significance in homeostasis. Using stringent criteria, the authors pictured the distinct circRNA expression signatures among seven types of solid tumors. The dysregulated circRNAs exhibited cancer-specific expression or shared common expression pattern across cancers, implying their diverse functions in cancer progression and their diagnostic potential in multiple cancers. Among the aberrant circRNAs, circLIFR showed an overall downregulation in tumors. Significantly, circLIFR was experimentally validated as a bona fide circRNA which inhibited tumor metastasis in vitro and in vivo


The derivative was shown to be non-toxic and safe, upon consumption  position in polysaccharides led to the development of various molecules exhibiting remarkable inhibition against anti-HSV in vitro  derived from a herbaceous perennial plant Radix Cyathulae officinalis Kuan demonstrated dramatic viral inhibition after phosphorylation as compared to unphosphorylated RCPS . Intereal., 2010). Anotheal., 2017). This hin vitro . An in-in vitro and has been shown to be effective against HPV by direct binding to viral capsomeres and further downregulating PI3K/Akt/mTOR pathway  on the cell surface. In an attempt to investigate this behavior, 3,6 O sulphated chitosan was explored al., 2018 [This isal., 2020 [This isal., 2020 [This isal., 2020; Woo et al., 2020). in vitro, and in vivo along with promising clinical trials are needed for better outcomes. Since future viral outbreaks are quite predictable, it is important to design a non-immunogenic, non-toxic and targeted drug delivery system to effectively deliver polysaccharide based antviral drugs to the infected population without any serious side effects and quicker recovery. The benevolent nature, biocompatibility, ease of availability, low cost and non-toxic profile of polysaccharides, claim their anti-viral potential with enhanced therapeutic response. The development and discovery of polysaccharide-based drugs, antibodies and vaccines may prove beneficial in arresting episodes confronted during acute respiratory distress syndrome, particularly in COVID 19 pneumonia. Chemical modification further ameliorates the challenges faced with unmodified polysaccharides. In fact, a combination of chemically modified polysaccharides and anti viral therapeutics, with a change in route of administration may play a decisive role in combating pandemics and epidemics. In a time where viral genome sequencing has unraveled sophisticated molecular pathways responsible for the survival of viruses, genomic epidemiology along with microfluidics can also play a crucial role in mapping evolutionary behaviour and understanding the virulent nature of mutating strains. Despite significant advances in the use of polysaccharides as excipients in recent years, the exact mechanism of viral interaction and signaling pathway is not clear. This necessitates delving into high throughput screening strategies for these dangerous viral infections for tangible patient outcomes. In fact, an amalgamation across different pharma sectors along with the latest AI  tools can fully leverage the antiviral potential of polysaccharides. Identifying potent biomarkers may also help, design polysaccharide-based anti-viral drug candidates to further gain an in-depth understanding and dynamics of infection.Polysaccharides can be future candidates for mitigating viral infections, but more Rabab Fatima, Parteek Prasher and Kamal Dua contributed equally.The authors declare no conflict of interest.


This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT’s opinion, the use of “biopsy-proven acute rejection” as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build. The approved histopathological endpoint for clinical trials of kidney transplantation is the presence or absence of biopsy-proven acute rejection (BPAR) . This enOver time, the spectrum of rejection has broadened, with distinctions made between two major subtypes: T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) . Deeper Furthermore, the strategy of performing protocol biopsies in the early years following transplantation has been adopted by several European centers, to detect subclinical rejection and guide ongoing patient management . It has • Suspicious (borderline) for acute TCMR (henceforth simplified to “borderline changes”)• Acute TCMR • Chronic active TCMR (caTCMR)• Acute/active antibody-mediated rejection (aAMR)• Chronic antibody-mediated rejection (cAMR)• Chronic active antibody-mediated rejection (caAMR).The classification of allograft rejection has often been modified over the years, such that six histological rejection phenotypes are widely described , 6:• SusBorderline changes represent less severe inflammation scores than aTCMR. The threshold of inflammation used for diagnosis of borderline changes  varies among centers, because between 2005 and 2017 the Banff Classification stated that retaining the i1 threshold for borderline changes with tubulitis (t) > 0 was permitted . In addiIn the 1990s, a diagnosis of aTCMR was based on a clinical definition  and/or a clinicopathological definition  , 13. TheThe impact of inflammation in atrophic areas (i-IFTA) on graft outcomes has been widely demonstrated , 14–16, per se. The response of caTCMR to increased doses of immunosuppressive therapy has not been studied function. Protocol (surveillance) biopsies are performed, per definition, at the time of stable graft function to detect subclinical inflammation  . IndicatFinally, although molecular diagnostics of kidney transplant rejection has been validated prospectively in a multicentric fashion  and is cESOT has come to the following conclusions:• The use of BPAR as an endpoint for clinical trials in kidney transplantation is no longer accurate.○ Using outdated and/or non-specific definitions, such as BPAR, compromises the future of high-quality clinical research, especially for interventions that are targeted at one rejection subtype.• Kidney transplant rejection should be classified by its phenotypes—borderline changes, TCMR, and AMR (the two latter having subtypes), and in relation to the nature of graft (dys)function .• The CHMP acknowledged that histological subclassifications of rejection have evolved during the last decade.• The CHMP agreed that the histological subtype of rejection is a useful specification and noted that this detailing might be very informative in profiling efficacy of immunosuppression.• The CHMP commented that the reason for undertaking a protocol or indication biopsy should be taken into consideration when defining endpoints for clinical trials.


Crop domestication is a co-evolutionary process that has rendered plants and animals significantly dependent on human interventions for survival and propagation. Grain legumes have played an important role in the development of Neolithic agriculture some 12,000 years ago. Despite being early companions of cereals in the origin and evolution of agriculture, the understanding of grain legume domestication has lagged behind that of cereals. Adapting plants for human use has resulted in distinct morpho-physiological changes between the wild ancestors and domesticates, and this distinction has been the focus of several studies aimed at understanding the domestication process and the genetic diversity bottlenecks created. Growing evidence from research on archeological remains, combined with genetic analysis and the geographical distribution of wild forms, has improved the resolution of the process of domestication, diversification and crop improvement. In this review, we summarize the significance of legume wild relatives as reservoirs of novel genetic variation for crop breeding programs. We describe key legume features, which evolved in response to anthropogenic activities. Here, we highlight how whole genome sequencing and incorporation of omics-level data have expanded our capacity to monitor the genetic changes accompanying these processes. Finally, we present our perspective on alternative routes centered on de novo domestication and re-domestication to impart significant agronomic advances of novel crops over existing commodities. A finely resolved domestication history of grain legumes will uncover future breeding targets to develop modern cultivars enriched with alleles that improve yield, quality and stress tolerance. Domestication refers to an evolutionary process causing remarkable changes in plant morphology and physiology in response to the selection pressures created by anthropogenic activities . The proPisum sativum L.), faba bean (Vicia faba L.), lentil (Lens culinaris L.), grass pea (Lathyrus sativus L.) and chickpea (Cicer arietinum L.) are some of the world’s oldest domesticated crops and arose in the Fertile Crescent of Mesopotamian agriculture. These legumes accompanied cereal production and formed important dietary components of early civilizations in the Middle East and the Mediterranean (Glycine max L.) and adzuki bean (Vigna angularis L.) accompanied cultivation with rice (Oryza sativa L.) in China, whereas domestication of common bean (Phaseolus vulgaris L.) and cowpea (Vigna unguiculata L.) occurred in Andes/Mesoamerica and sub-Saharan Africa, respectively. Other pulse crops such as pigeonpea (Cajanus cajan L.), mungbean (Vigna radiata L.) and urdbean (Vigna mungo L.) were domesticated in India  and barley (Hordeum vulgare), along with the grain legume crops such as pea and lentil. Wheat and barley were claimed to be originated in slightly drier, open parkland steppes along with wild grasses, while pulse crops including lentil, pea, chickpea and Vicia spp. originated in the clearings of nearby woodlands and rocky talus slopes , it has been suggested that soybean domestication occurred simultaneously at multiple sites  to its current status as a South Asian and spring-sown Mediterranean crop  has become a standard approach to study crop domestication and evolution. Linkage disequilibrium (LD) encompasses alleles at two or more loci having non-random association, and patterns of LD decay reflect recombination rates in the population. For instance, resequencing of 302 soybean accessions including wild, landraces and breeding lines revealed the extent of LD decay , with wiGenome sequencing of multiple accessions has revealed a loss of genetic diversity in breeding improved cultivars in different grain legume crops. For instance, the genome sequencing of pea and Pigeonpea revealed the most diverse single nucleotide polymorphisms (SNPs) in wild accessions in comparison to landraces and cultivars . The genC. reticulatum has early domesticated into desi type (common in South Asia and sub-Saharan Africa), whereas kabuli (common in West Asia and Mediterranean regions) were subsequently derived  involved in snare membrane traffic, wound-inducible protein and an amino acid transporter  and PAVs but lower CNVs as compared to kabuli . These f derived . The rolnsporter . Similartication . CNVs artication .FLP, MYB12) as the adaptive changes during shifting environments  influencing the two key flowering-related genes SOC1 and FT. The growing sequence data on whole genomes of diverse accessions will likely enrich the knowledge about the genetic underpinnings of the plant phenotypes that were changed during domestication and improvement of grain legume crops.The genomic evolution rate profiling (GERP) score reveals the genomic regions that remain evolutionarily constrained (GERP > 0) and indicates purifying selection, such as 29 Mb in chickpea  and 237.ronments . In commronments . With a ronments . The stuThe potential of CWRs and landraces has been historically recognized for supplying new genetic variation to plant breeding programs . The valCWRs often encounter broad and contrasting environmental conditions across their native range. Over evolutionary time, these exert differential selection pressure that leads to the formation of specifically adapted ecotypes. Drought is one of the main abiotic stresses acting in the Mediterranean and Middle East region, where progenitors of many cultivated crops occur and have to cope with water availability during the vegetation period.CWRs provide a key to counteract the effects of climate change on the world’s food supply. To fully understand and exploit this process, studies in the geographical centers of origin are needed that combine ecology, physiology and genetics. With modern genomics tools, geospatial analysis combined with systematic phenotyping, it is highly desirable to revisit wild accessions and prioritize their use for breeding tolerance to various stresses. In particular, some local adaptations found in CWRs might maximize fitness in specific habitats, especially in the current climate change context .Environmental conditions such as soil salinity, cold and drought stress represent a major constraint on agricultural productivity. Water availability is a primary factor controlling the distribution of vegetation over the earth’s surface. Crop yields are more dependent on an adequate supply of water than on any other single factor, and environmental stress  represents the primary cause of crop yields losses . Many otGmCHX1-conferring salt tolerance to wild soybean G. soja (Lens odemensis and Lens tomentosus) were identified as displaying tolerance to drought (Arachis duranensis) maintains a relatively high rate of transpiration and photosynthesis rate under dehydration treatment  mapping revealed a novel gene- G. soja . Similar drought , and ada drought . Reduced drought . Variati drought , and roo drought . Similarreatment . Adaptivreatment , where treatment . Wide vareatment . Recent ted crop .rhg1 and Rhg4 have been identified from wild soybean controlling resistance against the soybean cyst nematode (SCN), which is one of the major threats limiting soybean production  and drought was evident in a recent research (AsECHI) from Arachis stenosperma reduced the infection rate by 30% as well as accelerating post-drought recovery. In pigeonpea, CWRs are known to possess resistance against a variety of biotic and abiotic stresses  encompasses features that are absent in the wild progenitors or ‘differentially’ manifested in cultivated species, such as changes in seed retention, seed size, inflorescence and plant architecture and flowering synchronization. There is an ongoing debate about the number of domestication events and centers for a given crop. Two domestication centers have been reported for common bean: Central America and the Andes , and potGmHs1-1, encoding a calcineurin-like metallophosphoesterase transmembrane protein, was found to influence seed coat permeability in soybean  gene was implicated in seed coat permeability in common bean , and this gene not only represses Dt1 that prevents terminal flowering but also activates genes that promote flowering  is common and well conserved in legumes and cereals  and pea (Dpo) demonstrated it to be a monogenic trait; however, later several QTLs affecting this trait were also discovered  underlying flowering time are also known to affect flowering in soybean  in order to promote flowering. In course of narrow-leaf lupine domestication, this requirement has been removed and widely exploited by plant breeders to develop early-flowering varieties of L. angustifolius. It has been shown that the loss of vernalization requirement in narrow-leaved lupin is associated with a deletion in the promoter and de-repressed expression of a Flowering Locus T (FT) homolog , encoding a dirigent-like protein expressed in the sclerenchyma of differentiating endocarp and modulating the mechanical properties of the pod through lignin biosynthesis (C. arietinum ICC 4958 × C reticulatum ICC 17160) and intra- (ICC 4958 × C. arietinum ICC 8261) specific recombinant inbred lines revealed major QTL for flowering time in chickpea (GI (GIGANTEA) ortholog during chickpea domestication through conferring flowering time adaptation.In the legumes, single locus control of pod dehiscence was found in lentil , pea We and chicynthesis . Table 2chickpea . Like otchickpea , pea  and seed length (AhDPB2) , 62 SNPs showed association with frost tolerance and provided superior haplotypes associated with the frost damage (A genome-wide association study (GWAS) is an alternative approach to associate genomic variations with domestication phenotypes in diverse germplasm collection. GWAS of 203 accessions combined with transgenic and RNA-Seq experiments in groundnut facilitated the identification and validation of genes for seed weight ((AhDPB2) . Likewis(AhDPB2)  and a to(AhDPB2) . By usint damage . The cont damage  and PAV t damage  in soybet damage  correspot damage . Other Gt damage  and commt damage  and flowt damage , pod indt damage , pod mort damage  and seedt damage  in commot damage . The stuC. reticulatum supported its contribution to early phenology, crucial to transitioning from winter to summer crop  led authors to report a significant loss of diversity during domestication, and most of the diversity (87%) was found in the wild  than G. max . Decades of research have enlightened the impact of SVs  in crop evolution and agricultural adaptations. Compared to SNPs, SVs can directly alter the genic expression by modifying the copy number and can cause large-scale perturbations of cis-regulatory regions (CHS) gene expression in yellow soybean  and Arachis kempff-mercadoi ICG 8164 × Arachis hoehnei ICG 8190), respectively , and the QTL analysis identified 42 potential QTL governing significant PVs for plant growth habit, height, plant spread and flower color (P. fulvum or P. elatius) in the genetic background of P. sativum offer a valuable resource for genetic research and breeding  by using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) editing of key domestication loci such as fas, lc, CLV3 , an orphan Solanaceae crop, showed the potential of CRISPR–Cas9 editing for de novo domestication by altering one  was achieved by Vigna stipulacea.V. stipulacea, resulting in the recovery of mutants with notable reductions in seed dormancy and pod shattering. Given the species-rich legume family, there is large potential to domesticate novel legume crops for both human food and animal feed. This effort has been recently demonstrated in hairy vetch (Vicia villosa)  . Anothervillosa) , these pvillosa) .While legume CWRs have not yet been subjected to de novo domestication, several traits that could be targeted in these species spring to mind. Perhaps the first of these is seed shattering, which in e.g. common bean  as in ceThe process of redomestication represents an important opportunity for cultivated species to adapt to new ecotype. Besides de novo domestication that could deliver entirely new crops, the wild species or existing crops can be redomesticated by changing the artificial selection pressures toward plant traits catering to future requirements . At the Since the beginning of agriculture, grain legumes have been important ingredients as protein complement sources to starch-rich cereal diets. The domestication of cereal crops has been intensively researched, resulting in the identification and cloning of domestication genes. In recent years, carbonized remains and genetic studies have helped establishing the role of grain crops in old as well as new world agriculture. A very recent example of this is the identification of a WD40 gene as being important in the domestication of grain yield in both rice and maize with a wide range of other genes putatively also following this trend . As suchDomestication of cereals and grain legumes has shown different trajectories as exemplified from the time lines of grain size enlargement . GeneticIndeed, we are convinced that combined evidence from archeobotanical, pangenomes, multi-omics science and cultural shifts will enlighten future crop improvement strategies to rapidly develop modern cultivars of grain legume crops. That said, this will be no easy task and will certainly require both multi-disciplinary and multi-national approaches; however, in principle, the necessary technologies are all in hand and studies concerning the adaptation of our major crops to novel environments will undoubtedly help in efforts to create a more sustainable global agriculture that is more resistant to extreme climacteric events.pcac086_SuppClick here for additional data file.


Curricular intervention studies have examined if instruction in aging and gerontology affects undergraduates’ attitudes, knowledge, and perceptions towards older adults. However, less is known about curricular impact on undergraduates’ intentions to work with older adults. By identifying factors that increase undergraduates’ intentions to work with older adults we may elucidate meaningful points of intervention to enhance pursuit of careers in the geriatric workforce. The current study examined baseline data from a longitudinal study examining the impact of an upper-level adult development psychology course on student attitudes towards working with older adults. It was hypothesized that there would be positive associations between attitudes towards working with older adults, knowledge about aging, and positive attitudes towards older adults. Participants were 19 undergraduate students enrolled in upper-level undergraduate psychology courses. Participants completed validated, self-report questionnaires related to their attitudes towards working with older adults, ageism attitudes, and attitudes and knowledge about aging. Bivariate correlation analyses were used to examine cross-sectional associations among main outcome variables. More positive explicit attitudes towards older adults were significantly associated with more willingness to work with older adults . Additionally, knowledge of aging was positively correlated with perceived social norms around working with older adults . These initial findings suggest that knowledge and positive attitudes about aging may positively impact attitudes towards working with older adults. Future work will assess curricular impact on undergraduates’ intentions to work with older adults, as well as evaluate predictors of change in intentions.


Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis and should ideally be performed as a totally percutaneous procedure via the transfemoral (TF) approach. Peripheral vascular disease may impede valve delivery, and vascular access site complications are associated with adverse clinical outcome and increased mortality. We review strategies aimed to facilitate TF valve delivery in patients with hostile vascular anatomy and achieve percutaneous management of vascular complications. Minimally-invasive transcatheter aortic valve replacement (TAVR) has supplanted surgical aortic valve replacement (SAVR) as the preferred mode of treatment in the majority of patients with severe aortic stenosis ,2. The tFailure of vascular closure devices (VCD) to achieve access site hemostasis following valve implantation and sheath removal may lead to severe bleeding, as well as limb ischemia . PercutaCalcified, stenosed and tortuous ileofemoral arteries characterize patients with “hostile” vascular anatomy and may impede valve delivery and increase susceptibility to vascular injury during TAVR. In such patients, SAVR may potentially enable valve replacement without the need for instrumentation of the peripheral vasculature. However, patients with peripheral vascular disease often have co-morbidities which are associated with increased surgical risk and may therefore benefit from percutaneous valve delivery. Alternative vascular access approaches  were developed in order to enable TAVR in patients with hostile vascular anatomy in whom TF valve delivery was considered technically challenging. No randomized trials have compared these different approaches; however, the TF route is considered the least invasive. The aim of the present review is to summarize novel techniques which may facilitate totally percutaneous TF valve delivery.Peripheral vascular disease (PVD) is common in patients referred for TAVR ,12, and Vascular calcification ,24,25, tUse of VCD to achieve hemostasis decreases wound complications and duration of hospitalization compared to surgical cut-down ,31,32,33Early detection and rapid management of VC is crucial. Manual compression may achieve hemostasis in cases of minor access site bleeding, and protamine sulfate may be safely administered to reverse anticoagulation . Severe Percutaneous management of VC and vascular repair may be facilitated by placement of a 0.014″ 300-cm length “safety” wire within the femoral artery prior to puncture of the primary vascular access site . The safety wire is delivered via a secondary vascular access site  and is uThe contralateral femoral artery was traditionally used for secondary vascular access in TF TAVR procedures. Alternative secondary access sites include the ipsilateral distal branches of the femoral artery  ,41,42, rThe CFA is subject to repetitive stress and flexion at the hip joint. Implantation of balloon-expandable stents within the CFA is unsafe due to risk of stent fracture, compression, restenosis and branch occlusion ,47. NitiStents grafts (SG), which are covered with impermeable membranes such as polytetrafluoroethylene, may be used for excluding vascular tears and perforations and maintaining arterial integrity. Balloon-expandable SG, which were previously used for endovascular repair of iatrogenic vascular injury , have beStents were implanted in 10–24% of patients undergoing TF TAVR and achieved hemostasis in 98–100%. During follow-up, the stents maintained near-universal patency with a low rate of asymptomatic strut fracture. Anecdotal data suggests that repeat vascular access and deployment of a VCD may be possible within a vessel that was previously treated by SG implantation . A liberThe CFA should be punctured at least 1 cm above the bifurcation in order to enable SG implantation without compromising outflow to the superficial femoral artery or profunda. Decision to implant SG is usually made following sheath removal, when control angiography reveals evidence of VCD failure. Long sheaths  may be used for SG delivery; however, they require upsizing of the secondary vascular access . Alternatively, SG may be delivered by a sheathless technique in order to minimize vascular trauma at the secondary access site. Stent grafts are typically delivered antegradely, from the contralateral femoral artery . Alternatively, ipsilateral distal vascular access within the superficial femoral artery or profunda ,41,42 anPre-procedural assessment of the femoral artery anatomy may show that the vascular anatomy is unsuitable for deployment of a VCD. In some patients, attempts to perform pre-closure with a suture-based VCD at the beginning of the TAVR procedure, prior to sheath insertion, may fail. Performing TF TAVR despite the inability to utilize a VCD may necessitate surgical vascular repair of the femoral artery. Patients at increased risk for complications of vascular surgery may benefit from a percutaneous method for achieving access site hemostasis following valve implantation and sheath removal. We assessed the feasibility of a strategy of planned stent graft implantation within the femoral artery for achieving access site hemostasis in a cohort of patients undergoing TF TAVR, in whom vascular pre-closure was not possible  60]..60].These patients were considered at increased risk for complications of vascular surgery due to advanced age, frailty, co-morbidities, or immobility. Stent graft implantation achieved access site hemostasis in all patients. During follow-up, 30-day mortality was zero, one-year mortality was 27%, and none of the patients required additional vascular interventions.Recent evolution of techniques and devices for treating severely diseased ileofemoral occlusive vascular disease, as well as novel strategies for utilizing SG for management of access site vascular complications, offer the opportunity to expand the role of totally percutaneous TF TAVR to patients with PVD . A systematic approach to procedural planning and management of vascular complications increases the likelihood of procedural success .Development of TAVR systems with lower device profiles, as well as novel VCD designs with improved efficacy, may expand the role of TF TAVR and decrease the need for alternative vascular access in patients with hostile vascular anatomy.


Mitochondria regulate numerous cellular processes including metabolism, gene expression, motility and migration, as well as cell division, repair and death. Due to their ability to dynamically remodel, distribute throughout the cell, and interact with other organelles, mitochondria can perform its functions by acting locally or globally. The field of mitochondrial dynamics has thus grown from simple textbook observations of a static “kidney-bean” like energy producing structures to an organelle that works by dynamically changing its architecture and association with other organelles. The importance of the dynamic mitochondrial network and how integral it is to cellular function is highlighted by a growing list of diseases associate with defects in this process . This ReYu et al.). These data identify selective binding dynamics of DRP1 adapter proteins to explain their non-overlapping roles in DRP1 recruitment to mitochondria in healthy cells that gets disrupted in disease caused by the loss of adaptor proteins  to mitochondria by adaptor proteins . In theiproteins .2+ mobilization from ER to mitochondria. This was supported in cells from patients carrying OPA1 GTPase or GED domain mutations. Their study substantiates the role of OPA1 in modulating ER-mitochondrial coupling and shows even when mutant and WT OPA1 proteins are present together in patient cells, ER-mitochondrial Ca2+ homeostasis is disrupted, contributing to autosomal dominant optic atrophy .Unlike DRP1-mediated outer mitochondrial membrane (OMM) fission, Optic atrophy-1 (OPA1) regulates inner mitochondrial membrane (IMM) dynamics, mutations in which leads to dominantly inherited optic neuropathy that causes vision loss . Both OMBonjour et al. examined how the mitochondrial ultrastructure changes during mouse eosinophil maturation and in inflammatory disease. They performed high-resolution mitochondrial ultrastructure analysis using transmission electron microscopy (TEM) and 3D tomography. This uncovered a reduction in mitochondrial area by 70% during eosinophil development that was attributed to increases mitophagy in immature eosinophils. They show that mitochondria form extensive contacts with other mitochondria and cellular organelles at a higher frequency in immature versus mature eosinophils. During asthma-induced inflammation, mitochondrial cristae remodeling occurs and mitochondrial contacts with granules increases. This highlights cell-specific mitochondrial ultrastructure remodeling that is responsive to increased inflammation, expanding the growing body of work highlighting mitochondrial ultrastructural changes in immune cell activity.Complimenting the mechanistic studies of mitochondrial shape change, Willingham et al. review subcellular specialization of mitochondrial structure and function in skeletal muscle and how plasticity of these mitochondrial features regulates function and physiological adaptations of skeletal muscle . The review by Pangou and Sumara explore the connection between mitosis and cell division by discussing the regulation of mitochondria by mitotic machinery and how in turn mitochondrial function and inheritance regulates mitosis. They discuss the mitochondrial dynamics during mitosis and how its dysregulation is linked to diseases (Pangou and Sumara 2022). The discussion of mitochondrial involvement in cell division is also covered by Madan et al., who examine this for polarized epithelium and how mitochondrial dynamics and metabolism play a role during epithelial-mesenchymal transition and cell migration for wound healing, inflammatory responses and tissue remodeling . Extending this discussion to the pathological condition of tumor metastasis, Boulton and Caino have explored how the molecular mechanisms of mitochondrial dynamics affect the growth, metabolism, and invasiveness of tumor cells. They discuss how mitochondrial fission machinery regulates growth factor and ROS signaling that drive metastasis through regulation of tumor cell and its microenvironment (Boulton and Caino. 2022).Expanding on the Original Research, Review Articles included in this Research Topic provide a comprehensive overview of contributions of mitochondrial dynamics to various physiological functions. In their minireview, Together the primary research articles and reviews collected in this Research Topic highlight how control over the mitochondrial spatial, temporal and structural changes drive cell-type specific signaling, to support cellular function in healthy and diseased states. We thank the authors for their contributions and expert insights, the collection of which in this Research Topic will add new insights into the growing recognition of mitochondrial dynamics and its subcellular architecture in driving diverse physiological processes.


As working family caregivers navigate work and care responsibilities, the work environment may contribute to their psychological well-being and physical health outcomes. Working caregivers who provide multi-generational care  experience greater vulnerability when compared to non-sandwiched caregivers . This vulnerability could be mitigated by supportive work characteristics . Informed by the life course perspective, this study compared the psychological well-being and physical health of working sandwiched and filial caregivers, and the moderating role of work characteristics (decision authority and supervisor support). Sandwiched  and filial  caregivers from the Midlife in the United States (MIDUS-II) Survey provided information about their background, caregiving, employment, well-being, and health via a set of questionnaires and phone interview. Regression analyses showed that sandwiched caregivers exhibited lower levels of generativity than filial caregivers. Moderation analyses revealed that sandwiched caregivers with greater decision authority trended toward exhibiting greater autonomy than other caregivers. Sandwiched caregivers with greater decision authority also exhibited significantly less difficulty with instrumental activities of daily living (IADLs) than other caregivers. Finally, sandwiched caregivers with greater than average supervisor support trended toward exhibiting higher level of generativity as compared to other caregivers. Results highlight the impact of sandwiched caregiving on autonomy, generativity, and IADLs in the context of decision authority and supervisor support. Findings may inform workplace programs and policies aimed at enhancing caregivers’ sense of decision making and increasing supervisor support in order to promote caregivers’ psychological well-being and physical health.


Automatically synthesizing consistent models is a key prerequisite for many testing scenarios in autonomous driving to ensure a designated coverage of critical corner cases. An inconsistent model is irrelevant as a test case ; thus, each synthetic model needs to simultaneously satisfy various structural and attribute constraints, which includes complex geometric constraints for traffic scenarios. While different logic solvers or dedicated graph solvers have recently been developed, they fail to handle either structural or attribute constraints in a scalable way. In the current paper, we combine a structural graph solver that uses partial models with an SMT-solver and a quadratic solver to automatically derive models which simultaneously fulfill structural and numeric constraints, while key theoretical properties of model generation like completeness or diversity are still ensured. This necessitates a sophisticated bidirectional interaction between different solvers which carry out consistency checks, decision, unit propagation, concretization steps. Additionally, we introduce custom exploration strategies to speed up model generation. We evaluate the scalability and diversity of our approach, as well as the influence of customizations, in the context of four complex case studies. Motivation. The recent increase in popularity of cyber-physical systems (CPSs) such as autonomous vehicles has resulted in a rising interest in their safety assurance. Since existing tools and approaches commonly represent CPSs as (typed and attributed) graph models ).


Lower extremity ischemia due to extrinsic arterial compression by venous stent placement is a rare but increasingly recognized occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications.A 26-year-old with progressively enlarging pelvic sarcoma despite chemoradiation developed recurrent symptomatic right lower extremity deep venous thrombosis due to worsening mass effect on a previously placed right common iliac vein stent. This was treated with thrombectomy and stent revision, with extension of the right common iliac vein stent to the external iliac vein. During the immediate post-procedure period the patient developed symptoms of acute right lower extremity arterial ischemia including diminished pulses, pain, and motorsensory loss. Imaging confirmed extrinsic compression of the external iliac artery by the newly placed adjacent venous stent. The patient underwent stenting of the compressed artery with complete resolution of ischemic symptoms.Awareness and early recognition of arterial ischemia following venous stent placement is important to prevent serious complication. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb, prompt treatment with arterial stenting is recommended. Further study is warranted to optimize detection and management of this complication. Lower extremity ischemia due to extrinsic arterial compression by adjacent venous stents is a rare occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications including amputation. This case report describes a patient with pelvic sarcoma who developed lower extremity ischemia after the external iliac artery became compressed by an adjacent venous stent. Existing literature including risk factors and potential mechanisms are highlighted.A 26-year-old with progressively enlarging spindle cell sarcoma of the right pelvis despite multiple rounds of systemic and radiation therapy developed deep venous thrombosis and pulmonary embolism due to mass effect on the right iliac vein. This was treated with mechanical thrombectomy, inferior vena cava (IVC) and bilateral kissing common iliac vein stents, as well as initiation of therapeutic anticoagulation. The patient responded well until approximately two months after the procedure, where he presented to the emergency department with 1 week of worsening lower extremity swelling and pain. Physical exam was notable for diffuse pitting edema of the right lower extremity. Although the swelling limited mobility, there were no focal motor or sensory deficits. The extremity was warm and well perfused with 2 + doppler signals from the popliteal, posterior tibialis, and dorsalis pedis arteries. The left lower extremity was normal.Right lower extremity ultrasound demonstrated acute deep venous thrombosis of the common femoral vein extending to the calf veins. Computed tomography (CT) venogram demonstrated thrombus throughout the right iliac vein and IVC stents with compression of the external iliac vein by the enlarging pelvic mass Fig. . Given tWhile in the interventional radiology suite, posterior tibial vein access was obtained to infuse alteplase and perform venography, which demonstrated flow-limiting thrombus extending from the right popliteal to the common iliac vein. There was minimal flow to the IVC with extensive filling of collaterals Fig. . The popWhile in the recovery unit, the patient’s leg appeared mottled. Bedside doppler revealed diminished signals in the right popliteal, posterior tibialis, and dorsalis pedis arteries. After approximately 4 h the patient reported pain, decreased sensation to the dorsum of the foot, and impaired motor movement of the toes and ankle.A CT angiogram was performed, demonstrating high grade narrowing right external iliac artery adjacent to the newly placed right external iliac vein stent Fig. . There wThe patient returned to interventional radiology for arterial angiography. The left common femoral artery was accessed and a 7 French destination sheath was advanced proximal to the right external iliac artery. Angiogram demonstrated severe focal narrowing along the right external iliac artery adjacent to the external iliac vein stent Fig. . Two ovePost-procedure, there was return of 2 + doppler signals throughout the right lower extremity. The previously noted acute motor and sensory deficits resolved. In addition to continuing therapeutic lovenox, the patient was started on 75 mg of clopidrogel daily to maximize arterial stent patency. The patient experienced significant improvement of lower extremity swelling and pain. Comfort care measures were ultimately pursued given progression of cancer.There has been a growing interest in complex venous interventions, owing to device improvements and increasing evidence to support catheter-based therapies for appropriately selected patients (Vedantham et al. Early recognition of this entity is important, as long-term sequelae from untreated limb ischemia can be devastating. One report describes the need for transfemoral amputation and subsequent issues with wound healing which required additional surgery (Trinidad et al. In almost all published cases where ischemia was detected early, endovascular stenting of the compressed artery was effective for revascularization. We thus recommend angiography and stenting as the primary initial therapy. Since delayed diagnosis can have serious morbidity, there should be a low threshold to bring the patient to the angiography suite. If the situation is not emergent and the clinical picture is unclear, CT angiogram can be considered to rule out other potential causes of ischemia, such as hematoma or distal thromboembolism. Vascular surgery should also be engaged early if there is suspicion for compartment syndrome or the need for open revascularization (Filtes et al. Although the risk factors for this phenomenon have not been rigorously studied, there are common themes within the published literature. Case reports have described this complication among patients with active pelvic malignancy, previously irradiated fields, prior pelvic surgeries, or other inflammatory processes (Filtes et al. While there is no clear trend, use of certain stents may contribute to the occurrence of this complication. Case reports have described this complication in the presence of both covered and uncovered stents, as well as self-expanding and balloon-expandable stents (Filtes et al. This complication was also observed when using Viabahn self-expandable stents during a similar case at our institution, as well in another case report (Subramaniam et al. The most frequently reported location of arterial compression after iliocaval stenting is the external iliac artery (Filtes et al. This case report raises the question of whether routine assessment of lower extremity arterial supply should be performed prior to any iliac vein intervention. In our case, checking pulses prior to our venous intervention was valuable for rapidly diagnosing an arterial problem, since a dramatic loss of arterial doppler signal should not occur after a venous intervention. Since this is easy to perform, we recommend routine perioperative pulse checks for patients who undergo complex venous interventions. Intra-procedural pulse-oximetry monitoring of the toes may also be useful to quickly assess for decreased arterial perfusion and guide whether immediate angiography should be performed (Kwasnicki et al. Although severe stenosis may manifest with clinically overt signs of threatened limb, more subtle effects of ischemia may go undiagnosed or misattributed to other etiologies, such as post-thrombotic syndrome. Thus, more objective assessments of arterial perfusion using non-invasive vascular studies including ABIs, PVRs, and doppler ultrasound should be considered in high risk patients. Rigorous peri-procedural evaluation of patients with peripheral artery disease or diabetes may also be beneficial to identify subclinical cases of decreased arterial perfusion, so that future issues with wound healing can be minimized. Ultimately, more research is warranted to effectively diagnose and manage this complication.Extrinsic arterial compression secondary to venous stent placement is a rare but increasingly recognized complication following iliac vein stenting. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb prompt treatment with arterial stenting is recommended minimize serious long-term sequelae. Further study is warranted to optimize detection and management of this complication.


Persons with newly diagnosed Alzheimer’s disease and related dementias (ADRD) and their care partners confront multiple challenges. These challenges have been even greater during the COVID-19 pandemic, where supportive resources often are limited or even discontinued. We conducted semi-structured interviews with 21 care partners of persons who were recently diagnosed with ADRD (2019-2020) to explore their lived experiences of adjusting to the new role. Directed and conventional content analyses were used and were informed by the life course theory. Care partners perceived difficulty in accessing medical and social services for their loved ones, particularly during the pandemic. Despite experiencing distress, some care partners chose not to seek help for fear of contracting COVID-19. This study provides insights on the unmet needs of care partners during a pandemic and highlights that effective, long-term strategies are needed to continue providing person-centered care to persons with ADRD and their families.


Treatment of acute ischaemic stroke (AIS) focuses on rapid recanalisation of the occluded artery. In recent years, advent of mechanical thrombectomy devices and new procedures have accelerated the analysis of thrombi retrieved during the endovascular thrombectomy procedure. Despite ongoing developments and progress in AIS imaging techniques, it is not yet possible to conclude definitively regarding thrombus characteristics that could advise on the probable efficacy of thrombolysis or thrombectomy in advance of treatment. Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better treatment of AIS patients. In this review, what is known about the composition of the thrombi that cause strokes and the evidence that thrombus composition has an impact on success of acute stroke treatment has been examined. This review also discusses the evidence that AIS thrombus composition varies with aetiology, questioning if suspected aetiology could be a useful indicator to stroke physicians to help decide the best acute course of treatment. Furthermore, this review discusses the evidence that current widely used radiological imaging tools can predict thrombus composition. Further use of new emerging technologies based on bioimpedance, as imaging modalities for diagnosing AIS and new medical device tools for detecting thrombus composition in situ has been introduced. Whether bioimpedance would be beneficial for gaining new insights into in situ thrombus composition that could guide choice of optimum treatment approach is also reviewed. Occlusion of a cerebral artery by a thrombus results in acute ischaemic stroke (AIS). Treatment of AIS aims to recanalise the occluded artery, promptly and efficiently, either by intravenous thrombolysis via recombinant tissue plasminogen activator (r-tPA) or mechanical removal of the thrombus via endovascular thrombectomy (EVT). In most countries, less than 15% of AIS patients are able to avail r-tPA treatmentUntil recently, there was limited availability of the thrombi that cause strokes. Available samples were mainly limited to occasional postmortem tissue and the clots removed in the course of thrombectomy device clinical trials. Since the success of clinical trials demonstrating effectiveness of mechanical thrombectomy in AIS patients with large vessel occlusions, more occluding thrombi removed during EVT procedures are available for analysis, allowing us to gain insights into thrombus composition.Perhaps the most characteristic feature of AIS thrombi retrieved by thrombectomy is the marked heterogeneity observed. A range of studies have described gross characteristics such as size, shape, morphology, consistency .Using H&E staining, AIS thrombi can be broadly classified into three subtypes, RBC rich, fibrin rich, or mixed. H&E staining cannot differentiate between fibrin and platelets. Nonetheless, using H&E staining, initial studies found that the composition of AIS thrombi is highly variable .6–10et al demonstrated that MSB staining can reliably identify platelet-rich areas.Some studies have employed Martius scarlet blue (MSB) staining, which provides better differentiation between fibrin and platelet components.CD42b immunohistochemical staining was used to study the platelet organisation within thrombi. Platelets were observed covering the fibrin layers, located at the periphery of RBC-rich arteriogenic thrombi or were clustered within fibrin rich cardioembolic thrombi.Activated neutrophils release histones and granule proteins embedded in web-like assembly of DNA filaments called neutrophil extracellular traps (NETs), for killing pathogens. Recent data have shown that NETs actively take part in thrombus formation by interacting with RBCs, platelets and platelet adhesion molecules such as fibronectin, fibrinogen and vWF, aiding formation of the thrombus scaffold with fibrin meshwork.Although rare, occasionally AIS thrombi have components found in atherosclerotic plaques such as calcification, cholesterol crystals and arterial wall components.Other methods such as scanning electron microscopy (SEM), atomic force microscopy, fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy have also recently been used to study AIS thrombi.The TOAST  classification categorises ischaemic stroke based on aetiology into five subtypes: (1) large-artery atherosclerosis (LAA), (2) cardioembolism (CE), (3) small-vessel occlusion, (4) stroke of other determined aetiology and (5) stroke of undetermined aetiology/cryptogenic.The composition and structural arrangement of a thrombus, is governed by the local haemodynamic conditions during clot formation.Several studies have suggested that cryptogenic strokes are primarily cardiogenic in origin, based on histological analysisIt has been also observed that extent of WBCs in AIS thrombi can varyThrombus composition can influence the efficacy of thrombolysis by r-tPA. Previous research has shown that RBC-rich thrombi respond better to r-tPA than platelet-rich or white thrombi.A recent study that investigated arrangement of thrombus components speculated that RBC-rich areas which have thin fibrin arrangements might be most prone to degradation by r-tPA.SEM has advanced understanding of the characteristics of thrombolysis-resistant clot which was shown to have a thick, compact outer shell made of densely compacted thrombus components including fibrin, vWF and aggregated platelets and this made the thrombi less susceptible to thrombolysis.et al did not find any correlation of thrombus components with recanalisation after EVTThrombus composition may play an important role in successful removal of thrombus via EVT. A study by Ahn The mechanical characteristics of thrombi are related to composition. An in vitro study with clots prepared from human blood found that thrombi with RBC content of 20% or above have increased viscosity and elasticity compared with clots with low RBC content.Higher WBC percentage in thrombi has been shown to negatively correlate with recanalisation and clinical outcome such as National Institutes of Health Stroke Scale (NIHSS) score at discharge and modified Rankin Scale score upto 90 days.et al found a trend suggesting the presence of vascular wall components was associated with lesser recanalisation success.Calcified emboli are quite rare in AIS patients with large vessel occlusions, but when present, calcification is associated with poor recanalisation and higher mortality.Patients have the best outcomes after EVT if the entire thrombus is retrieved in a single pass.AIS thrombus can be identified by CT and MRI. However, studies investigating the association of thrombus imaging with recanalisation have largely utilised CT imaging . CT is mIsodense clots on non-contrast CT (NCCT) correlate with a high fibrin/platelet content and are more resistant to thrombolysis and EVT.The vessel sign observed on gradient eco imaging (GRE) in AIS patients is called SVS. The SVS on GRE imaging is defined as a hypointense signal that spreads outside the actual thrombus periphery. The SVS is observed in 50%–85% of AIS patients with large vessel occlusion, particularly in RBC rich thrombus, while a lack of SVS usually suggests presence of fibrin-rich thrombus .35Thrombus permeability or perviousness is the degree to which blood is able to flow through a thrombus structure. Thrombus perviousness is the residual flow that is quantified using simultaneous measurement of thrombus attenuation on NCCT and single-phase CT angiography, called ‘thrombus attenuation increase’ (TAI). Increased perviousness gives high TAI.Imaging characteristics such as HAS and SVS have been linked to stroke aetiology. Some single centre studies have correlated SVS with cardioembolic aetiology in AIS.The prognostic value of SVS for recanalisation is debatable. SVS has been variously shown to be a negative predictor of early recanalisation after IV r-tPA treatmentThrombus permeability is potentially an important predictor of AIS treatment. It has been associated with better functional outcome, smaller final infarct volume, and higher recanalisation following IA r-tPA or IV r-tPA.Imaging techniques are the best way of visualising thrombus in situ, and the only way to visualise thrombi in in vivo environments. In the case of thrombi dissolved by r-tPA or thrombi not retrieved via EVT, clot imaging is the only resource for characterisation. While post thrombectomy analysis of clot composition is very valuable to improving our understanding, EVT can damage or cause structural changes in the thrombus during the removal procedure.Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better guidance of device selection prior to EVT.Biological tissues possess electrical properties and these properties are dependent on morphological, physiological and pathological conditions of the tissue and the frequency of the applied electrical signal.The bioimpedance measured with applied alternating current varies with the frequencyElectrical Impedance Spectroscopy (EIS) is carried out by measuring the electrical impedance of biological tissues over a frequency range. Since the electrical response of tissues is determined by their cellular components and the dimension, internal structure and arrangements of the constituent cells, tissues with different morphological and physiological properties give rise to characteristic impedance spectra.Based on EIS principles, clinical applications have been developed, especially in the field of oncology. SciBase, Dilon Technologies, Zilico, are some of the companies that developed medical devices with CE and/or FDA (US Food and Drug Administration) approval. These devices  can discriminate healthy tissues from cancerous tissues  with high sensitivity and specificity.et al demonstrated that based on EIS measurements, blood clot analogues can be classified into RBC rich or platelet and fibrin rich clots.EIS-based sensors are being developed for blood components such as WBCsSome studies have also demonstrated the feasibility of utilising balloon catheters mounted with microelectrodes for EIS measurements. The integration of four microelectrodes onto a catheter is made possible using a flexible and ultralight polyimide foil. Using such a system in atherosclerotic animal models, intravascular EIS measurements differed significantly in aortic plaques compared with normal aortic tissues.In recent years, mechanical thrombectomy has facilitated the analysis of thrombi retrieved during the EVT procedure and marked heterogeneity has been observed. Restricted availability of thrombi other than ones found in LVOs that are easily retrievable limits the current knowledge of AIS thrombi. Further studies will improve understanding of aetiology and its correlation to thrombus composition and clinical outcome. New emerging methods such as EIS, could be beneficial for gaining new insights into pathophysiological mechanisms of thrombus formation and identifying clot characteristics in situ in the acute care setting, aiding in selection of better treatment options for the AIS patients.


Subjective age has traditionally been considered by comparing felt age to chronological age, with those who feel younger reporting more adaptive developmental outcomes. Here we consider a new approach: subjective age discordance, which compares felt ages to the ideal ages of participants. Across eight study days, 116 older and 107 younger adults reported their daily felt and ideal ages. On the majority of days, both older and younger adults idealized ages younger than they felt. The opposite pattern, idealized ages older than felt ages, was rare and primarily seen in younger adults. Days when felt ages were less discordant from ideal ages were characterized by higher levels of positive affect than days with greater subjective age discordance. These findings suggest that positive developmental outcomes can occur not only from feeling younger, but through a greater alignment of ideal and felt ages.


Pressure overload hypertrophy of the left ventricle is a common result of many cardiovascular diseases. Androgens show anabolic effects in skeletal muscles, but also in myocardial hypertrophy. We carefully reviewed literature regarding possible effects of androgens on specific left ventricular hypertrophy in pressure overload conditions excluding volume overload conditions or generel sex differences. Pressure overload hypertrophy (POH) of the left ventricle is a common result of diseases like arterial hypertension, aortic valve stenosis, hypertrophic obstructive cardiomyopathy or aortic coarctation and is associated with increased morbidity and mortality –4. Thus,via the enzyme 5 alpha reductase (via androgen receptors (AR), but DHT shows twice the affinity for the AR and a ten-fold more potent effect on signalling pathways when compared to Testosterone (Testosterone in the human body is mainly produced by the gonads (by the Leydig cells in testes in men and by the ovaries in women) and in smaller amounts by the adrenal glands in both sexes. Conversion to DHT takes place eductase . Both hoosterone . Both hoosterone . In humaosterone , 16. Totosterone . A thirdosterone .via androgen receptors (AR) and induce myocardial hypertrophy via two different ways: 1) in a DNA binding-dependent manner (genomic pathway) where androgens bind to the AR, translocate into the nucleus and act like a transcription factor or 2) in a non-DNA binding-dependent manner  where androgens bind to the AR and activate rapid 2nd messenger signalling cascades, for example . Next to low serum levels of DHT these patients showed low degree of left ventricular muscle mass despite severe aortic valve stenosis and pressure overload . Our finData from animal studies and the few existing human data suggest that anti-androgenic therapy has the potential to improve cardiac function and remodelling in heart failure and to reduce or prevent cardiac hypertrophy in pressure overload conditions. Next to the detrimental pro-hypertrophic cardiac effects, Testosterone replacement therapy has been associated with prostate cancer, polycythemia and obstructive sleep apnea and many long-term effects are still unknown , 45. ThuOn the other hand, excessive reduction of serum androgen levels should be prohibited, especially in male patients. Very low levels of Testosterone in elderly men with Testosterone deficiency have been associated with increased cardiovascular risk and mortality and positive cardiovascular effects have been described for Testosterone replacement therapy in these patients –49. TestThe study situation currently remains controversial and future studies are required to determine, whether and if yes what kind of anti-androgenic therapy might be a treatment option at least for time-restricted therapy in patients with severe AS waiting for surgical or interventional relieve of pressure overload.Testosterone and/or its active metabolite DHT increase the hypertrophic response of left ventricular myocardium to pressure overload in animal models and associations were seen in human subjects. Anti-androgenic treatment to lower Testosterone and/or DHT levels should be discussed as a possible treatment option to reduce cardiac hypertrophy; however, possible negative effects of low serum levels of Testosterone onto vascular and metabolic health have to be taken into consideration. Future studies should focus on cardiac-specific anti-androgenic therapy in order to prevent myocardial hypertrophy in pressure overload conditions without negatively affecting general patient health in women and men.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.