Computed tomography angiography (CTA) has been the gold standard imaging modality for vascular imaging due to a variety of factors, including the widespread availability of computed tomography (CT) scanners, the ease and speed of image acquisition, and the high sensitivity of CTA for vascular pathology. However, the radiation dose experienced by the patient during imaging has long been a concern of this image acquisition method. Advancements in CT image acquisition techniques in combination with advancements in non-ionizing radiation imaging techniques including magnetic resonance angiography (MRA) and contrast-enhanced ultrasound (CEUS) present growing opportunities to reduce total radiation dose to patients. This review provides an overview of advancements in imaging technology and acquisition techniques that are helping to minimize radiation dose associated with vascular imaging. Patient radiation exposure is a known consequence of several common forms of medical imaging but has been deemed acceptable in a variety of conditions where the benefit of diagnosing or excluding an underlying medical condition outweighs the potential adverse effects of patient radiation exposure. Computed tomography (CT) and CT angiography (CTA) are the medical imaging methods with the highest radiation exposure, accounting for approximately half of the total radiation exposure in the United States  Report No. 184) [Current generations of CT scanners generate peak energies between 80 to 140 kV, with the majority using a tube potential of 120 kV, according to the International Commission on Radiological Protection (ICRP) Publication 135 [A single CT examination can range anywhere from 1–30 mSv in adult patients depending on the type of scan, CT scanner, and the region of the body measured, while CTAs can reach 100 mSv in some cases . While avol). Some example reference values of CTDIvol include 25 milligray (mGy) for the adult abdomen, 15 mGy for the pediatric abdomen, and 75 mGy for the adult head [vol and the scanning length in centimeters (cm). Facility registries, such as the CT Dose Index Registry, as well as the development of guidelines (including the ACR Appropriateness Criteria), have been implemented to promote further radiation reduction throughout the medical imaging field [Commonly accepted radiation exposure limits for various examinations are developed by the ACR and must be validated regularly for accreditation for each CT scanner used at a given facility, termed the Computed Tomography Dose Index Volume (CTDIult head . Dose Leng field . Even wiT), a relative measure of the radiosensitivity of organs to radiation, include the stomach, colon, lung, bone marrow, and breast [Patients who undergo surveillance or postoperative scans are exposed to additional radiation even after the initial identification and intervention of the underlying medical condition. While ongoing surveillance scans are often indicated, the lifetime cumulative radiation exposure of continued surveillance scans may breach even the highest lifetime radiation exposure recommendations. Intraoperative exposure to radiation by fluoroscopy is another source of considerable radiation exposure used in a wide variety of procedures, including the guidance of intravascular catheters and for confirmation of orthopedic hardware placement. Organs with the highest tissue weighting factor  is commonly used to evaluate coronary artery disease (CAD) and is preferred over invasive coronary angiography for patients with low–intermediate risk of CAD . The useAs radiation reduction techniques continue to evolve in other areas of CT imaging ,14,15,16A literature search was performed using the PubMed database and Google  search engine. Databases were searched using the keywords “radiation reduction techniques”, “magnetic resonance angiography radiation reduction”, and “computed tomography angiography radiation reduction”. Some specific searches for relevant topics such as the new MAGNETOM FreeMax  magnetic resonance imaging (MRI) system was performed using Google, as well as further exploration of topics around the use of AI in radiation reduction techniques.The most efficacious strategies for radiation reduction adhere to the as low as reasonably achievable (ALARA) principle in which acquisition techniques are optimized to answer the clinical question, while reducing patient radiation exposure as much as possible .A simple but often overlooked method of radiation reduction includes reducing and/or optimizing the scan length, which has proven especially effective for radiation reduction in coronary CTA (CCTA) scans ,18. ScanAutomatic tube current modulation (ATCM) enables CT scanners to alter tube current based on density differences in tissue attenuation, utilizing lower tube current when possible and subsequently resulting in lower radiation exposure . Larger New, sophisticated CT image reconstruction techniques require less patient radiation exposure to produce diagnostic level imaging quality. Advances in imaging reconstruction due to increased computer processing speeds allow for increased image processing complexity while retaining acceptable processing times.Iterative reconstruction (IR) is one such example that reduces radiation exposure from 40–63% when compared to using filtered back projection (FBP) techniques for CCTA; new hybrid IR techniques are expected to further reduce dose exposure in the future ,21,22,23Other methods of radiation exposure reduction take advantage of the increased processing power now possible with modern computers, such as electrocardiogram (ECG)-controlled tube current modulation (ECTCM), a technique that reduces radiation exposure during periods of the cardiac cycle when the resulting image would be unused . More soAI shows promise as another method of radiation reduction through various methods but most notably in image reconstruction. Convolutional neural networks (CNN) are AI algorithms developed to recreate standard-dose images from low-dose computed tomography (LDCT) scans . Deep leAI is also able to reduce radiation exposure by automating CTA tube voltage by dynamically selecting the appropriate voltage based on the patient’s anatomy and size, all while maintaining adequate image quality . AnotherRadiation dose exposure reduction is also possible via the implementation of a dual-source CT (DSCT), which allows for faster image acquisition due to two detectors acquiring perpendicular images simultaneously while maintaining temporal resolution. DSCT is particularly effective in patients who cannot remain still . Using DAnother advancement in the field of CT is dual-energy CT (DECT). DECT is particularly advantageous in the assessment of pulmonary embolus (PE) and the evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) . StudiesImportantly, the photon counting detector in DECT machines can apply a threshold that enables the filtering of unwanted noise, allowing the scans to be performed at lower radiation doses . Some stVirtual monoenergetic images (VMI), acquired using DECT, involve using either the projection domain or image domain to generate superior, blended images of high and low energy acquisitions, taking advantage of the high contrast offered in low keV scans while also benefitting from the low noise of the high keV acquisition . VMI+, cDECT also offers an alternative to traditional contrast scans through virtual non-contrast images. These DECT scans are used to calculate the calcium score (CaSc) for coronary artery disease risk stratification. In the past, the level of radiation exposure via traditional angiographic imaging modalities led to this risk stratification method being downgraded . CalciumDECT is also under investigation as a method of evaluating myocardial ischemia. Using color-coded-iodine perfusion maps, DECT scans can serve as an indirect perfusion marker and provide functional information regarding the patient’s coronary artery disease. Such information further increases the utility of DECT when compared to traditional CCTA, which only includes anatomic information . Other sWhile many methods to reduce radiation exposure from CT or CTA scans have successfully limited radiation exposure, alternative imaging methods using non-ionizing imaging techniques can supplement, and in some cases replace, traditional irradiating scanning modalities. The ACR Appropriateness Criteria offers clinicians radiologist-approved imaging recommendations for various clinical indications, including a qualitative assessment of the amount of radiation exposure for a given technique, allowing clinicians to select viable alternative imaging methods which result in less or no radiation exposure .Magnetic Resonance Angiography (MRA) is a notable radiation-free alternative to CTA. Radiation exposure from CTA scans is significant, delivering some of the highest radiation dose exposure on a per scan basis of any medical imaging modality. MRA is capable of high-resolution cross-sectional, multiplanar imaging (often without contrast) in a wide variety of applications. In a meta-analysis comparing MRA with CTA, the results show that the two imaging modalities have the same diagnostic value for intracranial aneurysm evaluation, albeit with a limited sample size .Both non-contrast MRAs (NC-MRAs) and contrast-enhanced MRAs (CE-MRAs) offer unique utility based on acquisition methods. Advantages of non-contrast studies include the absence of concern for nephrogenic systemic fibrosis (a condition associated with some of the gadolinium-based contrast agents that may be used in contrast-enhanced MRA), the relative simplicity and non-invasive nature of the scanning procedure compared to scans with contrast, and rapid repeatability of the scans which is particularly beneficial if initial scans are nondiagnostic due to motion artifacts or technical issues . The abiWithin the MRA imaging modality, multiple non-contrast techniques are available based on the region of interest. Flow-independent MRA is often utilized for imaging slow blood flow through veins and diseased arteries with a tradeoff in imaging quality from artifacts generated by off-resonant regions . Flow-deFor patients with renal dysfunction, QISS was developed to evaluate peripheral artery disease (PAD) without the need for contrast material. Requiring only 7 to 8 min on average for a whole-leg exam, QISS drastically reduces scan time when compared to the time of flight (TOF) methods that frequently take an hour or more for a whole-leg exam. QISS is also less prone to artifacts than TOF-MRA, and portions of the exam acquired with motion artifacts can easily be repeated when identified, resulting in only a 1-to-2-min prolongation of the exam time. QISS has also shown promise as a non-contrast, radiation-free imaging technique in diagnosing pulmonary embolism with a sensitivity and specificity of 86.0% and 93.3%, respectively, in a recent study . The priA third non-contrast MRA technique is subtractive 3D MRA. The cardiac-gated subtractive 3D fast spin-echo technique provides image quality comparable with CTA without the off-resonance artifacts that are prominent with flow-dependent MRA techniques. Other subtractive methods include flow-sensitive dephasing (FSD) and arterial spin labeling (ASL). FSD takes advantage of flow-dependent signal reductions between peak systole and end-diastole, resulting in arterial contrast after dephasing gradients are applied along the vessel length. ASL, another subtraction-based imaging acquisition method, is most commonly used as an MRA equivalent of x-ray digital subtraction angiography (DSA) for perfusion imaging of the brain but is also capable of imaging the extracranial carotid arteries. New developments in ASL imaging, such as 3D pointwise encoding time reduction MRA (PETRA-MRA), are in closer agreement with DSA when compared to TOF-MRA in the evaluation of intracranial stenosis . AdditioThe final two notable techniques of non-contrast MRA acquisition include velocity-selective 3D MRA and phase contrast MRA. Velocity-selective MRA is beneficial in slow flow settings where alternative methods such as IFDIR and ASL-based MRA techniques may result in low penetration of tissues. A primary limitation of this method is that artifacts are prominent in a non-uniform magnetic field setting. Phase contrast is an advantageous technique in cardiac imaging, providing quantitative values for shunts and valvular disease. Phase contrast is unique amongst imaging modalities in that the more complex 4D (otherwise known as 3D cine) acquisitions are capable of simultaneously displaying vessel anatomy and flow rates. Like many other MRA techniques, phase contrast is primarily limited by lengthy scan times and the need for complex image processing.In some scenarios, contrast-enhanced MRA (CE-MRA) is a helpful technique for imaging flow-related phenomena . CE-MRA Cardiac MR (CMR) is an imaging modality commonly used for long-term surveillance of adult congenital heart disease (ACHD), which is preferred over alternative methods due to the lack of radiation as well as the ability to avoid the rib spaces  . CompareRegarding MRA performance, a systemic meta-analysis demonstrates sensitivity and specificity of 91% and 88%, respectively, for TOF-MRA of the extracranial arteries . HoweverOne common barrier to utilizing MRA as an alternative to CTA revolves around the availability and/or accessibility of scanners, as well as the relative difficulty that many claustrophobic patients experience due to the traditional scanner design. The prolonged scanning times of MRAs compared to CTAs create additional difficulty for some patient groups. With recent advancements in MR design and reconstruction, new scanners are attempting to mitigate many of the issues associated with MR, including increasing the bore size to accommodate larger patients and reduce claustrophobia. For example, the FDA recently approved a 0.55 Tesla (T) magnet with a larger bore design (80 cm). Importantly, this product has substantial cost savings compared to other scanners due to the lower field power, which allows the scanner to be lighter and easier to transport . AdditioWhile poor resolution has traditionally been associated with lower-powered magnets, some aspects of a low-field strength are beneficial to the image acquisition process . Low-fieContrast-enhanced ultrasound (CEUS) has many advantages over other imaging modalities, including low-cost, non-nephrotoxic contrast agents and a low rate of complications compared to iodinated contrast agents . CEUS isDynamic feedback, a feature unique to the ultrasound (and CEUS) modality, allows for real-time feedback that is particularly advantageous in targeted biopsies where examiners can distinguish between vascularized and non-vascularized tissue . This tyImportant limitations of CEUS include the intralesional gas formation, which limits the utility of ultrasound. Ultrasound utility is limited in areas where the acoustic window may be obstructed by rib shadows which may be further complicated by an intervening bowel gas as well as patient respiration and immobility . FurtherAs discussed previously, a variety of techniques have been developed to reduce radiation exposure that focus on the scanning modality itself. While these methods have been well-studied, other methods of radiation reduction that are unrelated to the imaging modality are effective and may be more easily to implement, especially when financial limitations are a limiting factor when attempting to reduce radiation exposure.In cases where regular surveillance of vascular pathology is required, performing surveillance scans using an approach that alternates between irradiating (CTA) and non-irradiating (MRA) imaging modalities may be a reasonable method to reduce radiation exposure in high-risk patients. As previously described in a publication regarding endovascular repair surveillance , alternaThe creation and implementation of CT imaging protocols requires a team approach, often made up of radiologists, physicists, and CT technologists. Studies have shown that the more individuals involved in the process, the more variable the radiation dose. Employing external medical physicists is associated with increased radiation exposure in lung cancer screening (LCS) exams compared to internal medical physicists, while using any type of medical physicist is associated with lower radiation exposure overall . FurtherPatients at risk of high lifetime radiation exposure should receive special consideration regarding imaging modality selection, as many may require long-term, regular screening for potentially life-threatening pathology.In children, radiation reduction is of paramount importance due to the detrimental effects that cumulative radiation exposure may have on a child’s development and risk of cancer. Kawasaki disease, which requires monitoring for evaluation of coronary aneurysms, can result in high radiation exposure in children as coronary CTA has been the predominant surveillance method . The JapGenetic aortic syndromes, the most common of which is Marfan syndrome, are genetic conditions that require regular imaging for monitoring of the aortic diameter, which is an important predictor of potentially life-threatening aortic aneurysms and aortic dissections . As a reVascular Ehlers-Danlos (previously Ehlers-Danlos type IV) is another aortic syndrome that requires special consideration because of the potential for high radiation exposure. Although no evidence-based guidelines have been developed, institutions have a range of screening recommendations for patients with Vascular Ehlers-Danlos, ranging from regular screening for vascular abnormalities of the arterial tree to a single transthoracic echo in adults with no further follow-up ,52. DoppLoeys-Deitz syndrome, another aortic syndrome, overlaps with Marfan syndrome and/or Vascular Ehlers-Danlos, depending on the specific subtype . Due to Turner syndrome is another condition in which cardiovascular imaging is recommended for bicuspid aortic valve and aortic isthmus stenosis, two congenital cardiovascular malformations that are commonly seen with Turner syndrome . The recBicuspid aortic valve, independent of patients with Turner syndrome, is the most common cardiovascular malformation with a prevalence of 1000–2000/100,000 . PatientOutside of genetic conditions, many patients may have more common conditions that require special consideration regarding lifetime radiation exposure. Radiation therapy can be a life-saving treatment for patients with a variety of malignancies, however the impact of cumulative dose should be considered when imaging these patients . Other pThrough various advancements both in imaging acquisition and processing, the average radiation dose has drastically fallen over the last decade. Various institutions have successfully established protocols that reduce radiation through a combination of decision-making algorithms and careful coordination amongst multiple clinicians involved in the individual’s care. CT technique remains the modality of choice for most indications related to vascular imaging. However, several advancements both with CT technology as well as alternative imaging modalities have contributed to opportunities for significant reductions in radiation exposure .DECT allows for more accurate tissue characterization while at the same time requiring lower maximum energy ranges when compared to traditional CT scans. Through this novel technique, a wide range of clinical applications show promise when imaged with DECT, including lung and myocardial perfusion studies, calcium subtraction imaging for coronary artery disease evaluation, detection of portal and deep vein thrombosis, and PE detection, all with benefits of lower or equivalent radiation exposure without the need for exogenous contrast administration.The development of the low-field MRI offers a radiation-free alternative that will gradually become more accessible to a larger subset of the population. By reducing setup costs and other barriers through the novel design of new scanners, MRI may become the imaging modality of choice in the coming years for a wide variety of clinical indications and various screening exams. In specific situations, such as the intensive care unit (ICU) and ED, smaller, portable MRI systems have been shown to be effective, improving efficiency by reducing personnel required due to the portability of the scanner while also improving patient care with a bedside solution that negates the potentially detrimental transportation of the patient that would have previously been a necessity.MRA has proven to be a reliable alternative for radiation reduction, particularly in scenarios where CTA may be traditionally deployed. Multiple studies have found that MRA is comparable to CTA in diagnosing various vascular pathology while offering superior image quality in certain situations such as in the setting of severe atherosclerosis and some metallic artifacts. New techniques allow for the dynamic assessment of blood flow in evaluating pathologic changes in the vessels. Other methods reduce scan time, further reducing the time discrepancy that remains a predominant critique of MRA compared to CTA’s rapid scan times. While CTA will likely remain the predominant modality of choice, advancements in MRA acquisition techniques continue to narrow the gap between MRA and CTA, offering a capable and radiation-free alternative for a variety of indications.Another promising radiation reduction development is deploying AI and scanner learning to acquire low-dose, diagnostic quality scans. With rapid advancements in DL algorithms, AI can reduce radiation exposure by improving the image quality of low-dose images while also reducing processing times compared to traditional iterative reconstruction techniques. Outside of the image quality domain, AI can improve patient positioning during the scan, optimizing the patient’s location within the scanner which reduces radiation exposure. The diagnostic yield of various exams can also be enhanced through AI, allowing clinicians to improve their decision-making process by leveraging the large volumes of data available.While reducing radiation exposure through various hardware and software advancements will continue to reduce total exposure, improving the decision-making process of ordering scans and reducing unnecessary scans is another method of reducing radiation exposure that should be considered. Making decision-making support systems using information technology available for clinicians increases the diagnostic yield of the scans ordered while also reducing both the exposure to the patient and the volume of scans at the medical center .Unfortunately, many medical imaging facilities continue to utilize legacy scanners that limit access to modern radiation reduction techniques. DECT-capable scanners have not been widely adopted as many facilities continue to use legacy CT scanners. MRI accessibility is even more limited due to the higher cost associated with this technology. The development of new image acquisition methods that could be applied to existing scanners to improve the diagnostic quality of low-dose scans may prove useful in situations where new equipment may be cost-prohibitive or financially impractical.Numerous benefits of CT often prevent consideration of other modalities. These benefits include the widespread availability of CT scanners in most hospitals  as well as other factors such as staffing and scan duration ,55. ThisGiven the widespread availability of CT and a variety of other factors already discussed, many trials and research studies have focused on CTA’s diagnostic performance and efficiency rather than MRA or other techniques. For example, CTA was the predominant imaging modality used to identify proximal large-artery occlusion in various trials where mechanical thrombectomy was shown to be superior to noninterventional approaches . CTA alsThe development of AI for widespread use also raises some concerns. Lack of verifiability across imaging platforms, as well as the subjective human ratings that are relied upon during the approval process for AI deployment, have been called into question . CollaboVascular imaging constitutes a robust volume of imaging in many modern radiology practices, ranging from smaller private practice settings to larger referral centers. Traditional methods for evaluating vascular pathology often involved high levels of radiation exposure to patients; however, modern techniques and advances in vascular imaging have significantly reduced radiation doses associated with this segment of diagnostic imaging. A variety of dose reduction techniques and strategies have been developed and applied to CTA imaging which remains the most accessible method to evaluate vascular pathology. Recent advances in alternative non-ionizing imaging modalities have either reduced and/or eliminated differences in sensitivity and specificity between CTA and alternative modalities. However, cost and accessibility remain potential obstacles to realizing the widespread use of these alternative modalities. In particular, technological advances in the sector of MRA imaging have been so rapid that research evaluating performance compared to CTA has been slow to catch up. As researchers further evaluate and confirm the performance of these advances in vascular imaging for both ionizing and non-ionizing radiation imaging techniques, radiologists and clinicians should expect patient radiation exposure associated with imaging of vascular pathology to continue to decrease.


A number of recent studies have shown that human exposures to a wide range of endocrine-disrupting chemicals (EDCs) may increase the risk of disease across the lifespan by altering the homeostasis or action of endogenous hormones, or other signaling chemicals of the endocrine system. Commonly investigated EDCs include chemicals widely applied in commercial and industrial products, such as per- and poly-fluoralkyl substances (PFAS), polychlorinated biphenyls (PCBs), bisphenol A (BPA), phthalates, and certain pesticides. Our understanding of human health risks associated with exposure to EDCs remains limited. The early development period  might be more vulnerable to exposures to EDCs, but depending on the outcomes, relevant exposure windows may include several periods throughout the entire lifespan. In this Special Issue, we include seven epidemiological studies that address different aspects of human health risks associated with exposures to EDCs.Two epidemiological studies assessed potential associations between EDCs exposure and human reproductive health effects. First, an Italian study considered serum and follicular level of phthalates and BPA among 122 women undergoing oocyte retrieval for in vitro fertilization [Next, a cross sectional study of 1058 Danish men age 18–21) evaluated whether the use of personal care products (PCPs) that potentially contain multiple EDCs affected semen quality [1 evaluatThe following two studies published in this issue evaluated the effect of EDCs on maternal health, including preeclampsia and adiposity. The risk of developing preeclampsia in pregnancy was evaluated in relation to exposure to PFAS in a case-control study from Sweden. The study includes 296 cases diagnosed with preeclampsia and 580 controls pregnancies without preeclampsia identified through the Swedish medical birth register . PFAS waA study in a population with a high prevalence of obesity from the Pacific Island nation of Samoa evaluated the association of dietary BPA exposure and adiposity among 399 mother–child pairs . The stuNext, we have also included two articles that assessed associations between EDC chemical exposures and neurological outcomes in children. A California study evaluated whether maternal pregnancy exposure to agricultural pesticide compounds affects offspring’s risk for cerebral palsy (CP) . CP is tAnother study from Taiwan examined childhood urinary levels of multiple EDCs, including several phthalates metabolites, para-hydroxybenzoic acids, and BPA, on the susceptibility to attention-deficit/hyperactivity disorder (ADHD) . ADHD isFinally, this issue also included a methodological study that explored the challenges when distinguishing the confounding or mediating role of obesity in epidemiological analyses that aim to estimate EDCs exposure effect on other chronic health outcomes . The stuIn summary, the seven manuscripts included in the present Special Issue highlight the complexity when studying human health effects associated with endocrine-disrupting chemicals. The included papers demonstrated small steps in our continued understanding of the exposure effects of various EDCs on human health. This area of research is far from complete and greater efforts would be needed from the scientific community to understand whether and how these extremely widespread chemicals may influence health and disease risk in the populations.


Ex vivo mitral models are fundamental to mitral research and this diligently designed study provides an apt reminder of the strengths of this modelling modality in enhancing our understanding of mitral disease processes and spawning research hypotheses especially in areas where the evidence base is limited such as PM rupture. This commendable hypothesis generating work suggests the presence of sub-phenotypic groups within those with PM rupture, the characterization of which could allow for more precise and efficacious interventional strategies and sets the stage for further study in this challenging research area. Given the acuity and rarity of PM rupture, such information would be difficult to derive from clinical studies.The anatomical and functional complexities of mitral valve pathologies render clinical decision-making and intervention challenging particularly in emergent settings such as acute papillary muscle (PM) rupture. Although rare since the advent of percutaneous coronary intervention, PM rupture carries a dismal prognosis, with a recent multicentre study published in this journal revealing an in-hospital mortality of 24.9% in those undergoing surgical intervention . Given tex vivo mitral modelling are also apparent. Indeed, porcine models are not patient specific and do not fully emulate the complex biomechanics and anatomical variations of human mitral tissue nor would they simulate the various aetiologies of PM rupture and the concomitant sequalae such as left ventricular dysfunction and arrhythmia. Validation of such models is difficult, thereby limiting their translational value to only experimental use. Large-scale use of animal tissue within ex vivo simulators may also be costly and carry ethical implications.Despite the robust study design, the limitations of ex vivo platforms, therefore enhancing their effectiveness. Indeed, it is unlikely that ex vivo platforms will be rendered obsolete with the advent of these novel technologies.The advent and rapid evolution of disruptive technologies in medicine—namely three-dimensional (3D) printing, computational modelling, machine learning and extended realities—and advances in cardiac imaging have the scope to revolutionize mitral modelling. Moreover, they bear the translational potential to facilitate ‘personalized’ cardiac care and improve clinical outcomes by offering patient-specific procedure planning, surgical simulation training and procedural augmentation. Such technologies are also capable of being integrated with et al. [By integrating volumetric cardiac imaging, material technologies and software engineering, 3D printing transforms digital objects into 3D replicas through multi-layered material deposition over a digitally defined geometry. Advances in cardiac imaging—notably in cardiac CT and 3D transoesophageal echo (TOE)—enable rendering of highly accurate 3D images of cardiac structures. Progress in software engineering, particularly with the integration of machine learning (ML), now enables highly accurate and rapid delineation of anatomical boundaries in a process known as segmentation [et al. . Such plThe domain agnostic nature of ML enables identification of complex associations within big data with the efficacy of such models increasing with volume of inputted data. The quantitative nature of structural heart imaging naturally lends itself to ML and such methods have found a myriad of applications in mitral modelling particularly in automating and enhancing mitral segmentation to rapidly produce accurate 3D mitral replicas in the quest for point of care 3D printing. ML methods and 3D printing have also been successfully integrated to produce a hyper-realistic simulation platform for training in minimally invasive mitral valve surgery .et al. where augmented reality optimized intraprocedural TOE guidance facilitated more safer NeoChord implantation in a porcine model [Extended realities technologies harbour promise in the arena of mitral valve modelling and intervention particularly in surgical training, virtual proctoring and procedure planning . There ine model .Despite the rapid evolution of disruptive technologies, there is cause for caution amidst this riot of innovation. These technologies are relatively nascent, costly and carry their own inherent limitations. Indeed 3D-printed mitral replicas are as yet unable to accurately model mitral tissue and the complexities of mitral biomechanics such as deformation. The accuracy of 3D-printed replicas is also dependent on the quality of cardiac imaging from which they are derived and despite significant advances in this area, important limitations still apply. Computational flow dynamics offer high fidelity simulation of stress and deformation, but widespread clinical application is stifled by cost and complexity. Meanwhile, extended reality technologies face technical challenges associated with interfacing high volume multimodality data and issues associated with motion induced sickness in operators. Headsets can be cumbersome and could cause procedural hindrance. Much of the research with these technologies comprises of small proof of feasibility studies and comparison between studies is challenging given their heterogeneity.In essence, disruptive technologies look set to continue their rapid evolution and play an instrumental role in the quest for personalized cardiac care; however, careful consideration is required to their limitations when contemplating widespread clinical translation. Pragmatism would dictate that hybrid modelling through integration of these technologies’ may optimize their efficacy and this may represent the next translational step in this exciting field.


Empathizing with others’ pain appears to recruit the whole pain matrix, including a collection of frontal regions involved in the affective, motivational, cognitive, and attentional dimension of pain.This research explored how the modulation of interoceptive attentiveness (IA) can influence the frontal  activity related to the emotional regulation and sensory response of observing pain in others.22 healthy participants were required to observe face versus hand, painful/non-painful stimuli in an individual versus social condition while brain hemodynamic response (oxygenated [O2Hb] and deoxygenated hemoglobin [HHb] components) was measured by functional Near-Infrared Spectroscopy (fNIRS). The sample was divided into experimental (EXP) and control (CNT) groups and the EXP group was explicitly required to focus on its interoceptive correlates while observing the stimuli.In the individual condition, higher brain responsiveness was detected for painful confronted to non-painful stimuli, and a left/right hemispheric lateralization was found for the individual and social condition, respectively. Besides, both groups showed higher DLPFC activation for face stimuli displayed in the individual condition compared to hand stimuli in the social condition. However, face stimuli activation prevailed for the EXP group, suggesting the direct interoceptive phenomenon has certain features, namely it manifests itself in the individual condition and for pain stimuli.We can conclude that IA modulation promoted the recruitment of internal adaptive regulatory strategies engaging both DLPFC and somatosensory regions towards emotionally relevant stimuli . Therefore IA could be trained for promoting emotion regulation and empathic response.


Sentinel lymph node biopsy (SLNB) has been the standard of care for clinically node-negative women with invasive breast cancer (IBC) and is also performed for women with ductal carcinoma in situ (DCIS) with high-risk features undergoing breast conservation surgery (BCS). Despite national guidelines, there is still controversy on whether to perform SLNB when the risk of metastasis is low or when it does not affect survival or locoregional control.National guidelines indicate that SLNB should not be routinely performed in women over 70 years of age with early-stage hormone receptor-positive (HR+) Her2 negative IBCSimilarly, one-third of ASBrS surgeons surveyed recommend SLNB for DCIS with high-risk features when guidelines advocate against it. Surgeons in academic settings were less likely to perform SLNB in this setting.Despite national guidelines, most surgeons favor SLNB in older patients with early-stage HR+ Her2 negative IBC. Clinical factors such as tumor grade, stage, and histology may be used to predict nodal positivity in this population to tailor the omission of SLNB to the subset with low-risk features.


Cancer among older adults is pervasive, putting excessive strain at the individual, caregivers, and wider society levels. In our symposium, we bring together researchers from varied disciplines—with a focus on easing the strain of cancer on older adults by identifying important gaps in care and developing and implementing innovative methods for improving health services. First, Carrion will discuss the multifactorial experience of fears and beliefs about cancer and cancer prevention in 57 older Latino men. Krok-Schoen will discuss the longitudinal association between religiosity and cognitive functioning among older adults with hematological cancers. Next, Seaman will discuss engaging hard-to-reach patients and those who underutilize the health system. Blackberry will then describe an implementation and impact framework of a five-year research program to improve care in older people with cancer. Lastly, Halpin will discuss the 36-month implementation of a video-based patient education program for patients with multiple myeloma who are preparing for autologous stem cell transplant. Understanding the development and implementation of programs aimed at improving health services among older adults with cancer will help improve understanding potential methods for identifying and addressing health services challenges in these populations.


Interactions between species above- and belowground are among the top factors that govern ecosystem functioning including soil organic carbon (SOC) storage. In agroecosystems, understanding how crop diversification affects soil biodiversity and SOC storage at the local scale remains a key challenge for addressing soil degradation and biodiversity loss that plague these systems. Yet, outcomes of crop diversification for soil microbial diversity and SOC storage, which are key indicators of soil health, are not always positive but rather they are highly idiosyncratic to agroecosystems. Using five case studies, we highlight the importance of selecting ideal crop functional types (as opposed to focusing on plant diversity) when considering diversification options for maximizing SOC accumulation. Some crop functional types and crop diversification approaches are better suited for enhancing SOC at particular sites, though SOC responses to crop diversification can vary annually and with duration of crop cover. We also highlight how SOC responses to crop diversification are more easily interpretable through changes in microbial community composition . We then develop suggestions for future crop diversification experiment standardization including (1) optimizing sampling effort and sequencing depth for soil microbial communities and (2) understanding the mechanisms guiding responses of SOC functional pools with varying stability to crop diversification. We expect that these suggestions will move knowledge forward about biodiversity and ecosystem functioning in agroecosystems, and ultimately be of use to producers for optimizing soil health in their croplands. Because soil microbes drive soil functioning, their diversity is a major target for improving agricultural soils, which have lost between one-third and one-half of their organic carbon relative to natural vegetation due to conventional management practices . Crop diLessons learned from plant and microbial ecology of natural/unmanaged systems is helpful in explaining site-level differences in relationships among plant diversity, microbial diversity, and ecosystem functioning of managed agroecosystems. In a grassland biodiversity experiment, positive effects of plant diversity on soil fungal diversity occur through increased aboveground biomass production and thus supply of organic substrates . This meZea mays L.), likely because corn produces higher amounts of biomass with low C:N ratio, which can contribute considerably to SOC accumulation  and/or soybean (Glycine max L.)  as a focal crop, (3) use Illumina next-generation sequencing to generate sequence data for bacterial and/or fungal communities in bulk soil, and (4) provide sequencing data publicly or by request. We specifically use studies that provide next-generation sequencing data, following the recent movement toward DNA-based analyses of microbial communities as a metric for soil health  crop diversification experiment in corn and soybean cropping systems in the southeastern United States . Along wJuglans regia L.)-based agroforestry on bacterial diversity are positive overall  alone or in a six-species mixture decrease SOC by about 20% relative to a fallow control  or wheat (Triticum aestivum L.) cover crop in the winter fallow corn-soybean cropping systems significantly decreases soil bacterial diversity  plots. One way to optimize sampling effort is to increase subsamples collected and homogenized for each plot. In the 2, and thus the numbers of composited subsamples for SOC  soils of a long-term tillage experiment , within- for SOC  should b for SOC  and coul for SOC . VerticaFigure 1K). We performed an additional power analysis to identify how many replicates it would take to detect a significant effect after only 5 years of agroforestry given the observed effect size, and found that replication would have to increase by two orders of magnitude  can prevent detection of significant changes in SOC and microbial community diversity. Soil microbial diversity, in particular, can vary significantly at local or field-scales . Howeveragnitude . Thus, wagnitude , 2H.diversified–meansimplified)/pooled standard deviation. Using these observed effect sizes and an alpha level of 0.05, we determined the achievable statistical power given a range of sample sizes from 2 to 100 +  is one factor to consider to robustly measure diversity of soil microbial communities. To determine how soil sample size influences the ability to detect crop diversification effects on soil microbial diversity, we conducted a power analysis of results from to 100 + . This anto 100 +  to detecAdditionally, when characterizing soil microbial communities, it is important to consider optimizing sequencing depth  and accounting for relic DNA. Inadequate sequencing depth would lead to underestimation of actual diversity, whereas excess sequencing depth would be a resource intensive effort. The case studies highlighted here obtained paired end sequence read lengths of 250–300 bases per sequence, which should be sufficient for 16S gene regions and for most ITS gene regions . However(A) indicates sufficient sampling depth. The absence of leveling off in (B) indicates insufficient sampling depth, which may hinder insights gained from this dataset about how soil microbial diversity responds to crop diversification. Given this variation in apparent soil microbial diversity in agroecosystems, future studies would benefit from pilot tests to determine the adequate sequencing depth for overall diversity in the systems.Sequencing depth for soil microbial characterization. To illustrate the importance of sequencing depth in understanding soil microbial diversity, we plotted species abundance curves of fungal amplicon sequence variants (ASVs) identified in Identifying coordinated changes (or lack thereof) in SOC and soil microbial diversity can advance our understanding of diversity-ecosystem functioning relationships in agroecosystems, but determining the mechanisms that underlie SOC changes can help us to explain such relationships. Carbon cycling frameworks have increasingly understood microbial influences on SOC storage, but reconciling this framework with changes to SOC under crop diversification remains a major challenge. That is, we have seen a common pattern where corn production systems accumulate more SOC than soybean systems. However, according to the Microbial Efficiency-Matrix Stabilization (MEMS) framework, higher-quality  litter (such as that of soybean) decomposes more quickly, thereby increasing readily available carbon , which can then be stabilized and protected through associations with the mineral soil matrix . This miTwo case studies presented here measure readily available fractions of SOC , which cRecent global analysis has identified strong positive linkages among plant diversity, soil microbial diversity, and SOC in agroecosystems, but these linkages at the site level are quite idiosyncratic. Here, we have discussed contingencies upon plant functional type, number of crop species, field location, and experimental duration in determining how soils respond to crop diversification. Overall, we have described the role of crop functional type (more so than number of species) in how soils respond to crop diversification, with corn contributing more to SOC accumulation in agroecosystems compared to soybean and wheat. Still, higher microbial diversity is not always an outcome of crop diversification or an indicator of increased SOC, and site-to-site and year-to-year variation can introduce significant inconsistency in the effectiveness for any one crop diversification strategy. Though crop diversification does not have consistent effects on soil microbial diversity, it does consistently shift microbial community composition. Further, soil microbial diversity has no strong associations with SOC within sites, but SOC is generally a significant predictor of soil microbial community composition. Thus, despite the limited scope of our analysis of five case studies, we find strong evidence that microbial diversity is a less important mediator of crop diversification effects on SOC compared to microbial community composition. Moving forward, given a combination of more subtle effects that occur in early years of implementation of crop diversification and inherent spatial and temporal variation in SOC and soil microbial communities, we need to optimize sampling efforts and sequencing depths that aid robust estimates of change. We also need to integrate agroecosystems into current theory on soil microbe-carbon interactions. Such efforts will improve our understanding of plant diversity-ecosystem functioning in agroecosystems.RW, SK, and SJ conceived the project. RW acquired and processed the raw sequence data with substantial input from SK. RW conducted statistical analyses. All authors contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Digital Mental Health holds strategic potential in fulfilling populations’ mental healthcare unmet needs, enabling convenient and equitable access to mental healthcare. However, despite strong evidence of efficacy, uptake by mental healthcare providers remains low and little is known about factors influencing adoption and its interrelationship throughout the Digital Mental Health adoption process.This study aimed at gaining in-depth understanding of factors influencing adoption and mapping its interrelationship along different stages of the Digital Mental Health adoption process.This work adopted a qualitative approach consisting of in-depth semi-structured interviews with 13 mental healthcare professionals, including both psychologists and psychiatrists. The interviews were transcribed and analysed thematically, following Braun and Clarke’s method.In this communication, we will describe how digital technology is currently used by clinicians to deliver mental healthcare. We identify potential factors influencing Digital Mental Health adoption and characterize the different identified stages inherent to this appropriation process: i) Pondering appropriate use; ii) Contractualizing the therapeutic relationship; iii) Performing online psychological assessment; iv) Adapting and/or developing interventions; v) Delivering Digital Mental Health interventions; and vi) Identifying training unmet needs. A discussion on how different factors and its interrelationship impact the adoption process will also be performed.By characterizing mental healthcare providers journey throughout the Digital Mental Health adoption process, we intend to inform ecosystem stakeholders, such as researchers, policy makers, societies and industry, on key factors influencing adoption, so policies, programs and interventions are developed in compliance with this knowledge and technology is more easily integrated in clinical practice.


Salmonella typhimurium were shown to exhibit increased MNase sensitivity specifically at genes implicated in immune responses. Increased sensitivity at the −1-nucleosome permitted transcription factor and RNA Pol II binding events. This system illustrates how cytoplasmic signals induce altered chromatin states to produce a specific cellular response to a stimulus. Innate immune activation is a longstanding model for inducible promoters, transcriptional activation, and differential nucleosomal sensitivity in response to immune activation and offers a model that may be largely applicable to other specific cellular responses including viral infection and cancer. Previous work has shown that early transformation events are associated with prolonged nucleosome occupancy changes that are not observed later in cancer progression. Herein, we propose a model in which we suggest that detailed studies of nucleosomal occupancy and sensitivity in response to specific stimuli will provide insight into the regulation of nuclear events in cancer and other biological processes.The nucleosome, consisting of ~150bp of DNA wrapped around a core histone octamer, is a regulator of nuclear events that contributes to gene expression and cell fate. Nucleosome organization at promoters and their associated remodeling events are important regulators of access to the genome. Occupancy alone, however, is not the only nucleosomal characteristic that plays a role in genome regulation. Nucleosomes at the transcription start sites (TSSs) of genes show differential sensitivity to micrococcal nuclease (MNase) and this differential sensitivity is linked to transcription and regulatory factor binding events. Recently, lymphoblastoid cells treated with heat-killed  The nucleosome has long been considered a regulator of nuclear events. Consisting of ~150bp of DNA wrapped 1.65 times around a histone octamer, the nucleosome serves as the functional subunit of chromatin –4. SimilThe availability of massively parallel sequencing technologies in the early 2000s allowed for more detailed studies that mapped nucleosome occupancy in a highly time-resolved manner and provided insights into the dynamics of nucleosome remodeling. Time-resolved studies demonstrated widespread transient changes in nucleosome occupancy in response to reactivation of Kaposi’s sarcoma associated herpesvirus (KSHV) to produce a transient intermediate chromatin conformation favorable to an immune response followed by a return to the basal state . SimilarThis type of transient remodeling may also play a role in response to other stimuli including viral infections and resulting immune-mediated pathologies like those seen in acute SARS-CoV-2 infections and persistent systemic symptoms classified as Post-Acute Sequelae of COVID-19 (PACS). Chromatin remodeling complexes are essential for viral infection and replication indicating a direct role for chromatin dynamics during viral infection . InitialSalmonella typhimurium. However, increased sensitivity at the −1 nucleosome in highly expressed genes is observed 20 minutes after stimulation which is consistent with the timeframe for the innate immune response to bacterial stimulation [Nucleosome mapping is often achieved by digesting crosslinked chromatin in micrococcal nuclease (MNase) to produce ~150bp fragments which correspond to nucleosome-protected immune-specific regions  Figure . Biochemmulation ,26. MNasmulation . The posGenomic instability and altered chromatin organization are the hallmark of the transformed phenotype and are associated with cancer progression. Features of chromatin organization  are regulated by ATP-dependent chromatin remodeling complexes . MutatioSalmonella example above. The longer-lived nucleosome sensitivity changes explain differential gene activation through altered regulatory factor accessibility in conditions, such as high-grade cancers, where nucleosome occupancy appears largely static.Early grade adenocarcinomas show widespread nucleosome depletion at transcription start sites particularly in genes associated with chromatin structure and cancer progression. While it is unknown exactly how long this remodeled state persists, an appealing explanation is that this remodeled state persists longer than physiologically expected due to dysregulation of ATP-dependent chromatin remodeling complexes. Consistent with this explanation, differential occupancy is reduced in higher grade tumors , hintingThe above observations suggest that measurements of nucleosome occupancy and sensitivity will provide valuable insights into gene expression and cell fate outcomes in cancer progression. We propose a model to explain these relationships . In this


Person-centered care (PCC), or delivery of care consistent with preferences, can improve outcomes for residents in long-term care (LTC). However, PCC has not been universally adopted. Few studies focus on measuring specific barriers to meeting resident preferences, hindering identification of actionable targets to improve PCC delivery. The purpose of this study was to develop and test the content validity of a survey that measures staff barriers to fulfilling resident preferences for daily care and activities. Item sets comprised of barriers and preferences were informed by a review of literature and a descriptive, qualitative study with 19 LTC staff. An expert panel (n=8) was convened to test content validity, and content validity indices (CVI) were calculated. The initial survey consisted of 12 item sets assessing whether knowledge gaps, resident characteristics , family, facility rules/policies, availability of options, or staffing/workload functioned as barriers to meeting resident preferences for daily care and activities . Revisions informed by expert feedback resulted in a total of 17 items sets. Second round testing with experts (n=10) revealed overall improved item sets . These findings indicate that the survey items have initial content validity in measuring staff barriers to meeting resident daily care and activity preferences. Further psychometric testing with LTC staff is needed prior to implementing the survey, which will represent the first tool of its kind for supporting measurement of staff-derived targets for PCC interventions and policy change.


Socioemotional selectivity theory postulates that limited future time perspective (FTP) motivates older adults to prioritize emotionally meaningful goals, explaining documented age advantages in emotional well-being. During the early months of the COVID-19 pandemic, we collected data from 945 community dwelling adults and 156 assisted living facilities residents living in the United States . Participants reported their FTP using the scale developed by Carstensen and Lang (1996), as well as the frequency and intensity of sixteen positive and thirteen negative emotions. Age association with limited FTP was comparable to past studies. Contrary to our hypotheses, limited FTP was associated with lower emotional well-being across ages and suppressed (rather than mediated) a general trend towards higher emotional well-being in older ages. Findings suggest that there may be conditions under which perceptions of limited time horizons have negative implications. Theoretical implications are discussed.


Medicaid Accountable Care Organizations (ACO) are increasingly common, but the network breadth for maternity care is not well described. The inclusion of maternity care clinicians in Medicaid ACOs has significant implications for access to care for pregnant people, who are disproportionately insured by Medicaid.To address this, we evaluate obstetrician-gynecologists (OB/GYN), maternal-fetal medicine specialists (MFM), certified nurse midwives (CNM), and acute care hospital inclusion in Massachusetts Medicaid ACOs.Using publicly available provider directories for Massachusetts Medicaid ACOs (n = 16) from December 2020 –January 2021, we quantify obstetrician-gynecologists, maternal-fetal medicine specialists, CNMs, and acute care hospital with obstetric department inclusion in each Medicaid ACO. We compare maternity care provider and acute care hospital inclusion across and within ACO type. For Accountable Care Partnership Plans, we compare maternity care clinician and acute care hospital inclusion to ACO enrollment.Primary Care ACO plans include 1185 OB/GYNs, 51 MFMs, and 100% of Massachusetts acute care hospitals, but CNMs were not easily identifiable in the directories. Across Accountable Care Partnership Plans, a mean of 305 OB/GYNs , 15 MFMs , 85 CNMs , and half of Massachusetts acute care hospitals  were included.Substantial differences exist in maternity care clinician inclusion across and within ACO types. Characterizing the quality of included maternity care clinicians and hospitals across ACOs is an important target of future research. Highlighting maternal healthcare as a key area of focus for Medicaid ACOs–including equitable access to high-quality obstetric providers–will be important to improving maternal health outcomes. Accountable Care Organizations (ACOs) are a payment and delivery model designed to incentivize the provision of high-quality care at lower cost. Evidence of reduced spending in Medicare ACOs compared to traditional payment models has prompted states to experiment with the use of ACOs in their Medicaid programs –4. PreliDistinct in structure from Medicare ACOs where Medicare enrollees with traditional Medicare assigned to ACOs can visit any primary care or specialist clinician accepting Medicare , MedicaiAs of 2020, over half of physicians nationally are participating in at least one ACO of any type with just over a quarter of physicians participating in a Medicaid ACO . PhysiciMost research on clinician participation in Medicaid ACOs has focused on primary care clinicians , but theAs alternative payment models, including ACOs, become more common in all insurance types, understanding the differences in provider network breadth in Medicaid ACOs is increasingly important to ensure patient access to care. In Medicaid ACOs, adequate networks of OB/GYN providers are essential to ensuring high quality care for women. In this study, we quantify maternity care provider inclusion in Massachusetts Medicaid ACOs, implemented starting in March 2018, and analyze differences in provider inclusion by specific Medicaid ACO type.Using publicly available provider directories for Massachusetts Medicaid ACOs and data on provider supply, we quantified inclusion of obstetrician-gynecologists (OB/GYN), maternal-fetal medicine (MFM) specialists, certified nurse-midwives (CNM), and acute care hospitals with obstetrics departments in Medicaid ACOs. We then compared the number and type of providers across ACO types, across ACOs within ACO type, and to the total number of providers within Massachusetts.In Massachusetts, Medicaid ACO models were implemented starting in March 2018 with two ACO distinct models available as of 2021 , 28. TheWe analyzed obstetric provider inclusion in the 13 ACPP ACOs and three PCACOs operating in Massachusetts Medicaid in January 2021. We analyzed the inclusion of OB/GYNs, MFMs, and CNMs using ACO provider directories available online between December 2020 and January 2021. Five ACPP ACOs provided print directories generated directly from online directories located on the ACO websites. Eight ACPP ACOs provided separate, distinct printed directories available on the ACO websites. The three PCACOs utilized the MassHealth provider network for specialists, and we used the MassHealth online directory for these ACOs. Enrollment data for each ACO is determined as of July 2018 .For ACPP plans, clinicians included in the analysis were those listed in the categories of obstetrician, obstetrician/gynecology, gynecology, or maternal-fetal medicine within the provider directories. For certified nurse midwives (CNM), the directories which included CNMs had a separate section listing those who were included. For directories including a provider identification number (such as an NPI), the identifier was extracted, and duplicates were removed to determine the total number of providers included in that plan. For all others, duplicates were removed manually based on clinician name. If provider directories included practice names, we did not count these practices towards the number of included clinicians; we checked a number of these by hand in each directory to ensure that the majority of clinicians practicing in those organizations were included in the provider directory and discuss in the results where there were any deviations from this. We were not able to include family medicine physicians who provide maternity care due to the difficulty of systematically identifying these specific physicians.For the PCACO plans, we searched the online provider directory by specialty for “Obstetrics (OB/GYN)” and included individual clinicians in the count. MFMs were not classified separately in the online provider directory but were included within OB/GYN provider listings. To determine MFM inclusion, MFM providers listed within the 2019 Massachusetts Registration of Provider Organizations Physician Roster (MA RPO) were manually identified within the covered Medicaid OB/GYN providers . The MA The Medicaid waiver implementing the Medicaid ACOs includes a policy that PCACOs may designate a “referral circle” of ACO-preferred specialists that patients may visit without a required PCP referral ; howeverThe total number of OB/GYNs and CNMs in Massachusetts for comparison to provider directories is based on estimates from the Area Health Resources File from the Health Resources and Services Administration . We calcWe used the MassHealth Enrollment Guide (January 2019) to determine hospital inclusion for each ACO, limited to in-state acute care hospitals with an obstetrics department that conducts deliveries . Acute cThe primary outcomes of this study are the number of 1) Maternity care clinicians including OB/GYN physicians, MFM physicians, and CNMs and 2) acute care hospitals with obstetrics departments included in each of the Massachusetts Medicaid ACO plan types.Descriptive statistics for ACO provider inclusion were calculated; these statistics give equal weight to each ACO. Comparisons were made between ACO types and to the number of practicing physicians in MA. For ACPPs, which have different numbers of included physicians, we compare the number of included clinicians to the ACO enrollment. All analyses were conducted using Microsoft Excel.Across Accountable Care Partnership Plan ACOs, there was substantial variation in number of providers included . The meaPrimary Care ACOs utilize the full Massachusetts Medicaid specialist network, and therefore all ACOs of this type have the same OB/GYN inclusion of 1185 OB/GYNs and MFM inclusion of 51 . In addiWe compared these included clinician numbers to the total practicing obstetric clinicians in Massachusetts according to the AHRF. The AHRF notes there are 1,046 OB/GYNs, which is higher than the number of OB/GYNs included in any ACPP provider networks; however, it is smaller than the number of OB/GYNs listed in the PCACO network. The number of practicing Maternal-Fetal Medicine from the MA RPO is 61. The number of practicing CNMs in Massachusetts from AHRF is 345.The percentage of hospitals with obstetrics departments included also varied substantially within and across ACO types . AccountFinally, we examine variation in provider inclusion in ACPP ACOs by enrollment. First introduced in 2011, Medicaid ACOs are a relatively new value based payment model, and there is limited prior research characterizing the breadth of provider networks in these ACOs . In thisThe few prior studies on Medicaid ACOs in maternal health care show Medicaid ACO participation resulted in an improvement of the timeliness of prenatal care initiation in the first trimester but did not increase the total receipt of adequate prenatal care ; state MAnother important finding is that some Medicaid ACOs did not include any CNMs, and the PCACOs did not easily identify any included CNMs. CNMs attend over 17% of births in Massachusetts, including almost 20% of births covered by Medicaid . MidwifeACPPs that had high numbers of member enrollment had correspondingly high levels of provider and hospital inclusion. However, among plans that had lower member enrollment, provider and hospital inclusion varied widely. MFMs are crucial for managing maternity care for high-risk patients, yet fewer than 10 MFMs were included in a majority of ACPP ACOs, particularly in ACPP ACOs with low member enrollment. This has important implications regarding access to care for Medicaid insured individuals. As many ACOs with low levels of enrollment are located outside of major metropolitan areas, a smaller network could lead to increased distances to the nearest provider, as well as fewer options in selecting a specific clinician. Maternity care availability (including providers and insurance coverage) in rural areas is critical for ensuring adequate perinatal care, and reduced access is an ongoing issue throughout the nation .The study had several limitations. First, given the known limitations of online provider directories , 62, ourIn this study, we examine variation in the maternity care provider inclusion in Medicaid ACOs in Massachusetts, which is critically important for access to care for Medicaid enrollees. We find substantial differences across ACO types and within ACO type. Understanding the role of maternity care provider inclusion in Medicaid ACO contracts and Medicaid risk adjustment and payment policy may be an important area of future research to understand incentives of Medicaid ACOs that improve maternal health care and health outcomes. Additionally, measuring the quality of included obstetric clinicians and hospitals, particularly for maternal healthcare, is an important area for ensuring equitable health care for Medicaid enrollees. As Medicaid ACOs expand nationally, ensuring that maternal healthcare is an area of focus–including sufficient and equitable access to high quality maternity care providers–will be important to ongoing efforts to improve maternal health outcomes.S1 TableNote: Directories were accessed in December 2020/January 2021. Links updated as of November 2022. Due to a change in insurer ownership, BMC HealthNet provider directories are no longer available online.(DOCX)Click here for additional data file.


This cross-sectional study examines the association between the complexity of consumer guidelines for COVID-19 vaccination and identification of eligibility. The US Centers for Disease Control and Prevention also released guidance on prioritization.2 The survey measured demographic factors, COVID-19 vaccine eligibility criteria, and perceived eligibility for vaccination. States a priori selected for this analysis based on having greater than 75 participants were the 5 largest states by population and Georgia (Georgia was oversampled). To determine participant vaccine eligibility, vaccine prioritization guidelines of each state were extracted from government communications  identified as female; mean age was 45 years . The In this study, higher guideline complexity was negatively associated with correct identification of COVID-19 vaccine eligibility during vaccine scarcity in the US. When developing guidance, health agencies must balance precision and clarity. Increased precision may lead to greater complexity and lower target audience comprehension. Our findings suggest potentially large public health implications for complex guidelines. This study is limited owing to ecological design, social desirability bias, and potential misclassification of vaccine eligibility owing to self-reported data.More complex vaccine guidelines were associated with lower participant comprehension, potentially hindering eligible persons from seeking vaccines during a period of scarcity. To optimize public health communication, brevity and simplicity should not be undervalued.


It has been reported that diabetes mellitus affects 435 million people globally as a primary health care problem. Despite many therapies available, many diabetes remains uncontrolled, giving rise to irreversible diabetic complications that pose significant risks to patients’ wellbeing and survival.In recent years, as much effort is put into elucidating the posttranscriptional gene regulation network of diabetes and diabetic complications; RNA binding proteins (RBPs) are found to be vital. RBPs regulate gene expression through various post-transcriptional mechanisms, including alternative splicing, RNA export, messenger RNA translation, RNA degradation, and RNA stabilization.Here, we summarized recent studies on the roles and mechanisms of RBPs in mediating abnormal gene expression in diabetes and its complications. Moreover, we discussed the potential and theoretical basis of RBPs to treat diabetes and its complications. • Mechanisms of action of RBPs involved in diabetic complications are summarized and elucidated.• We discuss the theoretical basis and potential of RBPs for the treatment of diabetes and its complications.• We summarize the possible effective drugs for diabetes based on RBPs promoting the development of future therapeutic drugs. According to a survey by the International Diabetes Federation (IDF), DM is a major health problem affecting 435 million people worldwide . In 20212O2) are important factors in pancreatic β-cell, functioning in cellular signaling processes and regulation of glucose-stimulated insulin secretion (GSIS) ; the National Natural Science Foundation of China .


Physical activity is beneficial for older adults to maintain health and help manage chronic diseases but relies on routine participation. Some older adults continue with physical activity behaviors as they age, whereas others are negatively affected by impaired functional abilities, physical disabilities, and unmet psychosocial needs. This symposium presents quantitative and qualitative data on physical and psychosocial factors that can influence physical activity among older adults with varying levels and types of physical abilities. The first presentation will focus on aging into the disability associated with knee osteoarthritis, the leading cause of mobility decline among older adults that generally onsets after the fifth decade of life. The second presentation will focus on aging with a disability, specifically how health perspectives evolve when aging with a spinal cord injury. The third presentation will highlight how the COVID-19 pandemic has influenced outdoor physical activity among older adults when indoor activities became limited. The fourth presentation shifts perspectives to clinicians, specifically physical therapists, to explore the needs for addressing physical activity in the clinic. The fifth presentation outlines a physical activity intervention program and its implementation for community-dwelling older adults. Together, these presentations will provide practical insights for designing a person-centered program to improve physical activity for older adults including those aging into disability or aging with disability.


Bothersome urinary symptoms plague many older adults and disproportionally affect women. Underreporting of symptoms and general stigma/embarrassment associated with incontinence has negatively impacted the availability of treatments, as research cannot be championed if the severity of the problem is not apparent. Available therapeutics have limited efficacy and are often not recommended in aged patients. Lower urinary tract function has a long and rich history in animal studies; while much of the underlying anatomy has been described, including neural control mechanisms, the impact of aging has only just begun to be addressed. Recent work has provided strong evidence that neural control over micturition is significantly impacted by aging processes. This mini review discusses recent findings regarding how aging impacts the neural control mechanisms of micturition. With increasing age comes an increased incidence of lower urinary tract symptoms (LUTS), most prevalent in women and institutionalized populations . The sevThe bladder demonstrates complex neural regulation of its function despite a seemingly simple design. Control over the urinary bladder occurs as both an involuntary reflex and a conscious process. In cortical regions of the central nervous system (CNS), cortical function acts to suppress the voiding reflex until micturition is desired . Conversvia both somatic (conscious) and autonomic (unconscious) pathways and has been previously well reviewed   as the bladder expands, and the level of afferent nerve firing is proportional to bladder volume. The PAG relays this information to the cerebral cortex in humans, allowing for conscious input over the voiding reflex  . The autg reflex . Higher Functional changes in the urinary bladder are common in older adults, regardless of if they are symptomatic. The phenomena of overactive bladder (OAB) and underactive bladder (UAB) describe symptom complexes; diagnosis of detrusor underactivity (DU) or detrusor overactivity (DO) require clinical urodynamic assessment . DU and Like many other faculties, the CNS suffers in the aged environment. Functional MRI (FMRI) studies have demonstrated decreased blood flow, brain shrinkage, and metabolic dysfunction in the brains of older adults . In oldeDuring urine storage, adrenergic (sympathetic) inputs from the hypogastric nerve act on beta-adrenoceptors in the bladder wall, inducing relaxation, and act on alpha-adrenoceptors in the urethra, inducing contraction. Together, this allows for accommodation of increasing bladder volumes while maintaining relatively low pressure. Adrenergic and cholinergic receptor expression decreases with aging at both the mRNA and protein levels . EmptyinLUTS are a common, costly problem: billions of dollars are spent annually on the treatment and management of incontinence and related urinary problems. Nearly half of women over 65 years experience urinary incontinence—allowing for acceptance of LUTS as “the new normal” with aging—yet many remain continent throughout their lives, implying simply possessing an old bladder is not the sole prerequisite for developing urinary dysfunction and/or symptoms. LUTS significantly decrease quality of life and are a driving force in institutionalization. Available pharmacologic therapeutics pose many unfortunate and undesirable side effects: anticholinergic medications, for example, have been associated with increased cognitive symptoms with little improvement in LUTS. Surgical interventions can be challenging in older adults, limiting the realistic use of neuromodulatory devices for sacral nerve stimulation.Aging negatively impacts function across many systems, including the CNS. Vascular deficits are observed with aging: ischemia in the brain and bladder have been demonstrated, undoubtedly affecting urinary function . Alterat


JCI, Hindy and colleagues report on their evaluation of a multi-ethnic cohort of over 5,000 participants without known CVD. High suPAR levels correlated with incident CVD and atherosclerosis. Genetic analysis revealed two variants associated with the suPAR-encoding gene (PLAUR) with higher plasma suPAR levels. Notably, a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that seen in atherogenesis. These findings suggest a causal relationship between suPAR and coronary artery calcification and have clinical implications that extend to inflammatory disorders beyond CVD.Atherosclerosis contributes to the majority of deaths related to cardiovascular disease (CVD). Recently, the nonspecific inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) has shown prognostic value in patients with CVD; however, it remains unclear whether suPAR participates in the disease process. In this issue of the  Despite decades of research and improvement in outcomes, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide . AtherosAtherosclerosis is a diffuse, slowly progressing disease that in most cases remains asymptomatic for decades. It begins with subendothelial accumulation and retention of low-density lipoprotein particles, triggering an inflammatory response . CirculaOver the last 10 years, soluble urokinase plasminogen activator receptor (suPAR) has emerged as a nonspecific inflammatory biomarker with predictive and prognostic value in patients with CVD . suPAR iJCI, Hindy et al. (PLAUR) gene associated with higher plasma suPAR levels. One variant (rs4760) was confirmed experimentally in vitro and in vivo to lead to higher suPAR levels. The authors very nicely demonstrate that expression of the rs4760 PLAUR missense variant in human embryonic kidney (HEK) cells in in vitro and in in vivo mouse experiments resulted in an approximate seven-fold increase in suPAR levels, providing strong evidence that the rs4760 variant caused the high suPAR levels observed in humans. Through Mendelian randomization, the authors found that suPAR levels, predicted by the specific missense variant rs4760, were causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease  mice that exhibited increased circulating levels of suPAR to mimic increased suPAR levels observed in the clinic. Genetic overexpression of suPAR in a murine model of atherosclerosis using Pcsk9-AAV coupled with a Western diet led to a two-fold increase in atherosclerotic plaque size with large necrotic cores and macrophage infiltration in the TgsuPAR mice compared with WT mice. The authors determined that, prior to atherosclerosis, the aortic tissue isolated from TgsuPAR mice secreted higher levels of C-C motif chemokine ligand 2 (CCL2)  and exhibited higher numbers of monocytes. Furthermore, monocytes isolated from the circulation and aortic tissue of TgsuPAR mice exhibited a proinflammatory phenotype with enhanced chemotaxis, which contributes to atherogenesis ..suPAR trThe clinical data demonstrating the causal relationship between suPAR and coronary artery calcification and the data for cumulative incidence of CVD events presented by Hindy and authors are powerful and striking . The aut


The authors had 5 indications for PLLA injections and used subjective before and after photographs to evaluate its effectiveness. It would have been powerful to see a more objective assessment of volume retention such as three-dimensional imaging or patient reported outcome metrics using validated survey instruments (Video). The authors present a retrospective review of 241 patients who underwent facelift surgery with fat grafting, associated with Poly-L-Lactic Acid (PLLA) injections for facial volume maintenance after surgery.An important detail of this study was that the authors used an off-label dilution of PLLA, a common practice in facial aesthetics, reporting no complications or nodule formation in this series. Integrating facial fillers into postsurgical maintenance regime is especially helpful in patients with very low body mass index and inadequate fat donor sites. This paper reflects current clinical facial aesthetic surgery practices on facial volumization. In addition to PLLA, in our practice and many others, the use of different filler types such as hyaluronic acid (HA) and calcium hydroxyapatite is also very helpful for ongoing facial volumization and rejuvenation.


Walking ability is a robust predictor of health outcomes in aging. Compelling evidence supports meaningful interrelations between walking and cognition, notably when the former is performed under dual-task conditions that place increased demands on attention and executive control resources subserved by the prefrontal cortex (PFC) . Indeed,2) and deoxygenated hemoglobin (Hb) and is uniquely suited to examine task-related changes in brain hemodynamic responses during active walking [Due to the limitations inherent in traditional neuroimaging methods such as magnetic resonance imaging (MRI), our ability to understand and quantify how the brain is functionally involved in gait control during active walking has been limited. Nonetheless, recent studies using functional Near-Infrared Spectroscopy (fNIRS), a noninvasive optics-based neuroimaging modality, have begun to shed light on the functional brain correlates of walking. This technology uses light in the near infrared range (650-950nm) to quantify changes in oxygenated  . Our stu2 levels in the PFC across experimental conditions were assessed during active walking using fNIRS Imager 1100 . Magnetic resonance imaging was performed in a 3 T Phillips scanner . The scanner was equipped with a 32-channel head coil. FreeSurfer software package (http://surfer.nmr.mgh.harvard.edu/) was used to extract cortical thickness measures in 68 brain regions (34 in each hemisphere). The results revealed that thinner cortex in specific regions in the frontal, temporal, parietal and occipital lobes as well as the cingulate cortex and insula was associated with inefficient increases in fNIRS-derived HbO2 from single to dual-task walking conditions, notably the analyses controlled for several covariates including gait and cognitive performance. These findings indicate that multiple brain regions are involved in volitional control of walking in older adults. Furthermore, reduced cortical thickness maybe an important causal factor implicated in neural inefficiency in aging and possibly in other clinical populations.Cortical thickness and gray matter volume are genetically and phenotypically distinct. Therefore, our recent investigation was designed to determine the effect of cortical thickness on changes in the hemodynamic response in the PFC across walking task conditions to further elucidate interactions between structural and functional brain systems of locomotion . Communi


Teaching Point: Cystic dystrophy of the duodenal wall is often associated with underlying heterotopic pancreas and easily assessed with advanced and noninvasive imaging modalities such as CT scan and MRCP. A 56-year-old man presented with recurrent epigastric pain, projectile vomiting, and weight loss. He had a history of chronic alcohol abuse and acute necrotizing pancreatitis one year prior.Physical examination revealed a tenderness with sensation of induration in the epigastric region.Laboratory tests showed high level of lipase 870 U/L; (870 UI/L) other results were unremarkable.Contrast-enhanced computed tomography (CT) scan  showed aCDDW is a rare condition characterized by the presence of cysts within thickened duodenal wall. It often reflects cystic and inflammatory changes of aberrant pancreatic tissue into the duodenal wall, also referred to as pancreatic heterotopia . CDDW ocContrast-enhanced CT scan and magnetic resonance imaging (MRI) are helpful for this challenging diagnosis. Demonstration of mural thickening, stenosis of duodenal lumen, and cysts within the duodenal wall or in the paraduodenal groove are the key features. Small remnants of pancreatic tissue within duodenal wall having the same morphological and hemodynamic behavior as normal pancreas parenchyma may be detected. MRCP is superior in demonstrating dilatation of small pancreatic ducts into pancreatic remnants .ERCP remains the modality of choice in confounding cases. It may confirm the intramural location of the cysts and demonstrate signs of chronic pancreatitis. Using a fine-needle aspiration, ERCP may rule out duodenal adenocarcinoma, which is the main differential diagnosis of CDDW. Groove pancreatitis still the main complication of CDDW. in such cases, conservative treatment is recommended. However, surgical options such as pylorus-preserving pancreatectomy and the Whipple procedure are necessary to alleviate recurrent symptoms .


Widowhood is associated with decreased emotional well-being, particularly increased depression. Prior research suggests that religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine different dimensions of religiosity. This longitudinal study analyzed data from the 2006-2018 waves of the nationally representative Health and Retirement Study (HRS). Ordinary least squares (OLS) regression analysis was used to examine the relationship between widowhood and depression as well as the role of religiosity as a moderator of this association. Analysis was stratified by gender to further explore these interactions. Results show that men and women show similar levels of depression at widowhood, but men are far less likely to be depressed prior to widowhood. Women also show a better recovery pattern over time post-widowhood. Furthermore, religiosity (particularly attending church) is an effective way of coping with widowhood and mitigating depression for both genders. However, men are significantly less religious than women. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. Practical implications of this study include intervention development around increased screening and treatment for depression for widowed older adults  as well as connecting this vulnerable population with resources. These findings may also inform program outreach (such as hospice bereavement services) that aim to facilitate healthy grieving among widowed older adults.


Dyadic coping is a daily interpersonal process that married couples use to manage stress and maintain their marriage. However, little is known about its mediating role in the association between empathic response and marital quality among same-sex and different-sex couples. This study aimed to examine the extent to which dyadic coping mediates the association between empathic response and marital quality, focusing on middle-aged men and women in same-sex and different-sex marriages. We used dyadic data from the Health and Relationships Project (HARP), including 124 gay, 171 lesbian, and 124 straight couples. Results from the actor-partner interdependence mediation model (APIMeM) showed that dyadic coping within couples mediated the association between empathic response and marital quality for all couple types . More empathic response was associated with better dyadic coping, which led to higher marital quality. While such mediated paths did not differ significantly between gay and lesbian couples, direct associations between empathic responses and marital quality were only significant among lesbian couples. Additionally, there were gendered patterns within straight couples; while female spouses’ empathic response was associated with their and their male spouses’ marital quality through the couple’s dyadic coping, such a mediated path was not significant for male spouses’ empathic response. These findings suggest dyadic coping as an effective strategy for enhancing marital quality among same-sex and different-sex married couples, but the mediating role of dyadic coping is gendered in different-sex marriages.


With a rapidly aging global population, declines in cognition and functional abilities are an increasingly salient challenge and fear among many older adults. Researchers and clinicians often study changes in cognition and changes in functional limitations as separate trajectories although they frequently co-occur. In this study, we used two-stage structural equation modeling (SEM) to estimate longitudinal trajectories of cognitive and functional limitations using data from the Health and Retirement Study (2010-2016) . First, individuals’ longitudinal factor scores  were estimated for cognition  and functional limitations . A bivariate latent trajectory model was then fit to these scores. Model fit was acceptable . Parameter estimates showed that, on average, cognition declined slightly (-.08SD/decade) and functional limitations increased gradually (0.38SD/decade). Importantly, individual cognitive declines were significantly correlated with increases in functional limitation . This study fills an important research gap by using advanced statistical modeling (bivariate latent growth models) to examine the joint trajectory of cognition and functional decline which underscores the need to consider the interplay of these two abilities. Methods that quantify both individual and group trajectories can aid in better identification of aging patterns and lead to new ways of thinking about interventions to reduce the burden of concurrent decline.


Accumulating evidence indicates the existence of cancer stem cells (CSCs) sub-populations which fuel cancer growth and maintain stemness in different cancers. In addition to the genetic and phenotypic variabilities that differentiate CSCs from non-CSCs counterparts, CSCs adopt a flexible metabolic strategy to sustain their oncogenic and stemness properties, in order to survive and propagate in a hostile tumor microenvironment (TME). TME factors and metabolites exert context-dependent influence on cancer stemness. In addition, the metabolic landscape in TME is complicated by the crosstalk between CSCs and tumor-infiltrating cells. In this review, we will summarize the metabolic interaction between CSCs and various microenvironmental factors and review how this interplay regulates cancer stemness and tumorigenesis.An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment. Emerging evidence has suggested that tumor cells inside a tumor bulk are heterogenous with variable genetic, phenotypic and functional profiles . Among wCSCs reside in the tumor microenvironment (TME) where heterogeneous cell populations interact with one another . The intReprogramming cellular metabolism is considered as one of the core hallmarks of cancer ,16, by wExtracellular metabolites could exert either tumor-promotive or -suppressive effect in different cancers . Their a+CD117+ CSCs isolated from epithelial ovarian cancer patients showed increased glucose uptake while CSC phenotype could still be maintained under glucose deprivation environment [+ liver CSCs [Glucose, as the primary energy-producing metabolite, has been shown in different cancers to either promote or suppress CSCs. A study observed that hyperglycaemia resulted in enhanced invasion and stemness of breast CSCs by reducing the tumor suppressing microRNA miR-424 . Howeverironment . Similarver CSCs . These sAmino acids are another important group of metabolites which influence CSC stemness . GlutamiExtracellular lactate impacts cancer cells and CSCs through diverse mechanisms ,32,33,34In addition to glucose, amino acids and lactate, lipids also play critical roles in regulating the stemness trait of CSCs. In ovarian CSCs, the provision of exogenous fatty acid sources such as palmitoleic acid and oleic acid rescued CSCs from ferroptosis-induced cell death which was resulted from the inhibition of fatty acid lipogenesis enzyme stearoyl-CoA desaturase (SCD1) . In relaCSCs consume metabolites in the TME, at the same time CSCs also actively remodel the TME by their altered metabolite secretome in order to establish a supportive ecosystem for tumor initiation and progression . Under hKetone bodies, comprising of acetone, acetoacetate and beta-hydroxybutyrate (β-HB), possess both pro-tumor and anti-tumor properties . IncreasMetabolic plasticity could be observed in CSCs exhibiting flexible energy metabolic strategy, that enables them to cope with energy demands in response to changing nutrient availability and environmental stress  54,55,5,555,56. Under hypoxia, CSCs rely on glycolysis rather than OXPHOS to maintain their survival . Zhou etAcidic extracellular microenvironment, termed acidosis, is another physical environmental factor that influences CSC metabolism and functions ,69,70,71In addition to the alteration of physical properties of the TME, extracellular metabolites also contribute to the reprogramming of CSC metabolism. High glucose concentrations in the culture media promoted glucose metabolism in pancreatic and ovarian CSCs as evident by the activation of glucose transporter 1 (GLUT1) . In anotThe reprogrammed metabolic strategies in CSCs represent therapeutic opportunities. Drugs targeting glucose metabolism exert effect on glycolytic CSCs, as exemplified by the use of 2-DG ,78,79. ODiet determines the nutrient availability in the microenvironment where CSCs are exposed to, that in turn alters CSC metabolism .+ intestinal stem cell pool through the activation of peroxisome proliferator-activated receptor-related signaling pathway [+ CSCs pool and promoted tumorigenesis through JAK2/STAT3 signaling in colon cancer [+ CSCs [High fat diet has been correlated with higher cancer incidence and worse prognosis , and it  pathway . In oral pathway . In high pathway . Similarn cancer . Moreove [+ CSCs .Increased dietary intake of cholesterol and high cholesterol level have been implicated to facilitate tumor development and progression . Ehmsen Other types of diets have also been implicated in regulating CSCs. For example, a fasting-mimicking diet was observed to lower the glucose level and reduce the expression of stemness markers in breast CSCs . AccumulResults from the above studies indicate that dietary metabolites possess either promotive or suppressive role in the maintenance of CSC phenotypes in various types of cancers. Deciphering the mechanisms of such dietary effects on CSCs would shed light on novel therapeutic opportunities.The presence of heterogeneous cell populations within the tumor bulk are well characterized in different cancers ,94. CSCsCancer associated fibroblasts (CAFs) are fibroblastic cells residing in the TME that possess regulatory functions on cancer cells and CSCs . CAFs fu+ liver CSCs induced tumor angiogenesis [Endothelial cells (ECs) are functional cells that line the vascular system and are recruited to the TME for angiogenesis ,107. Unlogenesis . Wang etogenesis . Similarogenesis . In glioogenesis . Despite+ tumor-infiltrating T cells shifted their metabolism from glycolysis towards fatty acid catabolism [Immune evasion is one of the major hallmarks of CSCs . The mettabolism . Furthertabolism . The inttabolism . Proteintabolism ,125,126.tabolism . HoweverThe TME is comprised of various cellular and non-cellular components which reside with CSCs in the tumor bulk and continuously affect and modify the behaviors of CSCs. Metabolic plasticity displayed by CSCs enables flexible switching of their metabolic strategies to accommodate and survive in the hostile TME. In reverse, CSCs produce and secrete various proteins and metabolites to influence the neighboring microenvironment. This bidirectional interaction not only sustains the aggressive tumor behaviors but also protects and enhances tumor survival in response to stress and environmental insults.Given the importance of metabolic reprogramming in the maintenance of cancer stemness, elucidating the underlying molecular mechanisms which drive the metabolic plasticity of CSCs will likely reveal novel metabolic vulnerabilities and therapeutic targets to combat CSC-driven tumor development and progression. Current research efforts have been put to identify activated or mutated metabolic enzymes which play roles in promoting certain metabolic pathways to support cancer development and progression. Clinical trials with the use of small molecular inhibitors to target different metabolic enzymes has been underway . MetformDespite the enthusiasm of the development of metabolic therapies to target CSC metabolism for cancer treatment, concern and criticism were raised regarding the validity of experimental results using in vitro culture which deviates from the physiological environment . In part