The proportion of patients with breast cancer extending adjuvant hormone therapy beyond 5 years has increased dramatically in recent years, which is associated with improved patient outcomes. Clinical guidelines have recommended patients with high-risk breast cancer to extend adjuvant hormone therapy beyond 5 years. However, the prevalence, predictors, and outcomes of extended adjuvant hormone therapy in the real world remain unknown. By linking six Swedish health registries, we prospectively followed 13,168 patients with breast cancer (2005–2020) from their first prescription of tamoxifen or aromatase inhibitors and categorized them as extending or not extending adjuvant hormone therapy. Cox regression analysis was used to investigate whether extended therapy was associated with breast cancer outcomes. Among patients with breast cancer who were recommended to extend adjuvant hormone therapy by the national guidelines, the proportion of women who extended therapy increased 5 folds during the past 10 years, reaching 80.9% during 2018 to 2020. Patients were more likely to extend therapy after completing 5-year adjuvant hormone therapy if they were young , had positive lymph nodes , had high tumor grade , received chemotherapy , had first-degree relatives who died from breast cancer , or had a high income . Extended use of adjuvant hormone therapy was statistically significantly associated with improved disease-free survival . This study provides real-world evidence showing the use and improved breast cancer outcomes of extended adjuvant hormone therapy beyond 5 years.The proportion of patients with breast cancer extending adjuvant hormone therapy beyond 5 years has increased dramatically in recent years, which is associated with improved patient outcomes. Adjuvant hormone therapy for 5 years has been the standard of care for patients with estrogen receptor–positive breast cancer in the past several decades. However, after finishing the standard 5 years of adjuvant hormone therapy, some patients still have a high risk of distant recurrence during 15 years of follow-up [from 13% to 41% depending on tumor stage ]. TherefClinical trials have linked extended duration of adjuvant hormone therapy with better breast cancer outcomes , with a Using data from several Swedish health registers, this population-based study aimed to (i) examine the prevalence of extended adjuvant hormone therapy and how it changed over time; (ii) identify clinical characteristics and patients’ factors that determine the use of extended adjuvant hormone therapy; (iii) investigate the association between extended adjuvant hormone therapy and survival outcomes in a real-world setting.The Regional Ethical Review Board in Stockholm, Sweden, approved the study. The Stockholm-Gotland Quality Register for Breast Cancer  hold detailed information on tumor characteristics and treatments for all patients with breast cancer diagnosed in the Stockholm-Gotland region since 1976 . The SweUsing the unique Personal Identification Numbers , we linkDiscontinuation of adjuvant hormone therapy was defined as having intervals between any two consecutive refills of tamoxifen or aromatase inhibitors exceeding 6 months during the first 5 years . In SwedAmong patients who finished the 5-year adjuvant hormone therapy and remained free of recurrence at the end of 5-year therapy, we defined whether the patients extended their therapy or not. Specifically, extended therapy was defined as continuing the therapy for ≥6 months and filling ≥2 prescriptions of tamoxifen or aromatase inhibitors beyond the 5-year adjuvant hormone therapy. Information on the prescription of tamoxifen or aromatase inhibitors was obtained from the Swedish Prescribed Drug Register.Information on age, tumor size, lymph nodes status, tumor grade, progesterone receptor status, HER2 status at diagnosis, and treatments was retrieved from the Stockholm-Gotland Quality Register for Breast Cancer. Information on therapy type at baseline was retrieved from the Swedish Prescribed Drug Register. Family history of breast cancer or death from breast cancer at diagnosis was obtained by linking the Multi-Generation Register to the Swedish Cancer Register and the Cause-of-Death Register. Socioeconomic status at diagnosis, including education and personal income, was retrieved from the Swedish Longitudinal Integrated Database for Health Insurance and Labor Market Studies. Income was measured using average 5-year income before diagnosis and categorized into three groups according to tertiles.Disease-free survival was defined as time to local recurrence, distant metastasis, contralateral breast cancer, second primary cancer (excluding skin cancer), or death from any cause. We also considered overall survival, i.e., time to death from any cause. Information on distant metastasis, local recurrence, and contralateral breast cancer was retrieved from the Stockholm-Gotland Quality Register for Breast Cancer. Information on second primary cancer was retrieved from the Swedish Cancer Register. Information on the death was retrieved from the Swedish Cause-of-Death Register.Patients were followed from the first prescription of tamoxifen or aromatase inhibitors until local recurrence, distant metastasis, contralateral breast cancer, death, emigration, completion of 5-year treatment or end of the study period , whichever came first, to define treatment discontinuation.Among patients who continued adjuvant hormone therapy in the first 5 years, patients were followed from the end of 5 years to 5.5 years to define extended adjuvant hormone therapy.Patients were followed from the end of 5.5 years since treatment initiation until death, emigration or end of the study period , whichever came first, to define the event for the corresponding survival analysis.Kaplan–Meier analysis was performed to estimate the cumulative rate of continued use of adjuvant hormone therapy over 10 years. We used age-adjusted and multivariable-adjusted logistic regression to identify predictors for extended adjuvant hormone therapy. Kaplan–Meier analysis was used to estimate rate of disease-free survival and overall survival among patients who extended adjuvant hormone therapy and those who did not. Cox regression model was used to investigate the association of extended adjuvant hormone therapy with disease-free survival and overall survival, adjusting for age at diagnosis, calendar period of cancer diagnosis, tumor size, lymph node status, tumor grade, progesterone receptor status, chemotherapy, radiotherapy, Charlson Comorbidity Index at therapy extension, education and income at diagnosis. We conducted subgroup analyses by repeating the Cox regression analyses within strata defined by tumor size, lymph node status, tumor grade and type of adjuvant hormone therapy at baseline.All analyses were performed using SAS software  and Stata software , at a two-tailed alpha level of 0.05.Data underlying this article were provided by the Socialstyrelsen and Statistics Sweden by permission, and cannot be shared publicly due to the Swedish Secrecy Act. Researchers may apply for data from the Socialstyrelsen, and the Statistics Sweden according to Swedish law.Among 4,660 patients who finished the 5-year adjuvant hormone therapy, 1,386 (29.7%) patients extended their therapy . ConsistThis population-based study investigated the use of extended adjuvant hormone therapy beyond 5 years in clinical practice. We found that the proportion of women who extended adjuvant hormone therapy increased 5 times in the last decades, both among those who met and those who did not met the extension criteria in clinical guidelines. Patients with worse tumor characteristics , receiving chemotherapy, or having first-degree relatives dying from breast cancer were more likely to extend their adjuvant hormone therapy beyond 5 years. Extended adjuvant hormone therapy was associated with better disease-free survival.Tamoxifen users with positive lymph nodes have been recommended to receive extended therapy since 2010 . In our Aromatase inhibitors users have been recommended to use extended therapy since 2018 . HoweverPatients with breast cancer with chemotherapy were over 5 times more likely to receive extended adjuvant hormone therapy than those without chemotherapy in our study. Receiving chemotherapy reflects worse tumor characteristics, such as positive lymph nodes, large tumor size, high proliferation rate and/or positive HER2 status . This rePatients with breast cancer who had first-degree relatives dying from breast cancer had 84% higher odds of extending adjuvant hormone therapy beyond 5 years. These patients are generally expected to be highly motivated and thus may prefer to extend their therapy when offered. Furthermore, clinicians may also take the family history of death from breast cancer into account, considering the previous studies showing that breast cancer survival is associated among relatives . ExtensiOur study provides real-world evidence showing that extended adjuvant hormone therapy beyond 5 years may improve breast cancer outcomes. We observed a 28% improvement in disease-free survival among patients who extended therapy, which was comparable to the effects observed in clinical trials . Our stuWhile extended adjuvant hormone therapy is associated with reduced risk for breast cancer events, it may also increase the risk of other diseases such as cardiovascular diseases and bone fractures . TherefoThe following limitations in our study should be mentioned. First, the association between extended adjuvant hormone therapy and breast cancer outcomes may be confounded by indication, because patients with worse tumor characteristics were more likely to extend therapy. However, this confounding would likely attenuate rather than amplify the observed association. We thus view our observed associations as conservative. We also adjusted for tumor characteristics and treatments to minimize its influence. Second, by using the Prescribed Drug Register, patients might only have a refill record but not take the drug. Third, because patients with breast cancer were recommended to extend their adjuvant hormone therapy only in recent years, we were unable to investigate the long-term health effect of extended adjuvant hormone therapy .In summary, the proportion of patients with breast cancer extending their adjuvant hormone therapy beyond 5 years have increased dramatically in recent years, both among patients who meet and those who do not meet the current therapy extension criteria in clinical guidelines. Further studies are needed to determine the factors that can be used to identify patients who are likely to benefit from extended adjuvant hormone therapy.Supplementary DataClick here for additional data file.


Primary cardiac tumors represent 0.1% of all cardiac tumors, making them a rare pathologic phenomenon. The second most common cardiac tumors are papillary fibroelastomas, which also represent the most common valvular tumors. This report examines a rare case of a patient that underwent resection of papillary fibroelastoma with simultaneous Cox-Maze IV procedure for treatment of atrial fibrillation. This 67-year-old male patient was initially scheduled for transcatheter ablation for treatment of rate-controlled atrial fibrillation. During a pre-procedural trans-thoracic echocardiogram, it was discovered that the patient had a moderately sized pedunculated mass on the aortic valve, suspicious of papillary fibroelastoma. Despite the patient having no history of embolic events or aortic insufficiency from the papillary fibroelastoma, the transcatheter ablation procedure was canceled. He was referred to cardiothoracic surgery for further evaluation, and it was determined that this patient was a candidate for papillary fibroelastoma resection along with Cox-Maze IV procedure for atrial fibrillation. Primary cardiac tumors are rare entities with an estimated incidence of 0.1% of all cardiac tumors . CardiacUnlike primary cardiac tumors, atrial fibrillation is far more prevalent and is the most common cardiac arrhythmia . It is eThis report examines a rare surgical case of a patient that underwent resection of papillary fibroelastoma with concomitant Cox-Maze IV procedure for atrial fibrillation.A 67-year-old male patient with past medical history of rate-controlled persistent atrial fibrillation, hypertension, hyperlipidemia and type II diabetes mellitus was scheduled for elective transcatheter ablation for treatment of atrial fibrillation. However, during pre-procedural trans-thoracic echocardiogram, a pedunculated shimmering mass measuring 16 × 8 mm was discovered on the noncoronary cusp of the aortic valve, representing a papillary fibroelastoma . This fiThe surgical procedure began with the papillary fibroelastoma resection via aortotomy. After the patient was placed on cardiopulmonary bypass and the heart was arrested, a minor aortotomy incision was made and the mass was seen attached to the noncoronary cusp of the aortic valve. The mass was shaved off and sent for further pathologic evaluation , which lThree weeks following discharge after surgery, the patient was seen in the cardiothoracic surgery office for a follow-up appointment. Physical evaluation and assessment of the patient revealed that the patient had a regular rate and rhythm rather than an irregularly irregular rhythm associated with atrial fibrillation present during preoperative evaluation. An echocardiogram was performed, demonstrating a well-functioning aortic valve. The patient was also seen in clinic three months following surgery, and electrocardiogram again demonstrated normal sinus rhythm. At this time, patient no longer required amiodarone for atrial fibrillation, and is scheduled for another follow-up appointment in three months.This surgical report highlights the rare case of a patient undergoing resection of papillary fibroelastoma of the aortic valve along with Cox-Maze IV procedure for atrial fibrillation. Both the presence of papillary fibroelastoma and atrial fibrillation represents two unique risk factors for cerebrovascular accidents.Cerebrovascular accidents are a notable symptom of papillary fibroelastomas, which may be due to embolization of the tumor itself or embolization of a platelet fibrin clot that develops secondary to the tumor. Therefore, prompt resection of papillary fibroelastomas upon identification is the recommended therapy . When coWhile there is literature that demonstrates the short-term success of the Cox-Maze IV procedure in terms of treating atrial fibrillation, further studies must be conducted to assess long-term outcomes as well as studies demonstrating reduction in cerebrovascular accidents in these patients.


Neurons in the central nervous system (CNS) communicate with peripheral organs largely via the autonomic nervous system (ANS). Through such communications, the sympathetic and parasympathetic efferent divisions of the ANS may affect thermogenesis and blood glucose levels. In contrast, peripheral organs send feedback to the CNS via hormones and autonomic afferent nerves. These humoral and neural feedbacks, as well as neural commands from higher brain centers directly or indirectly shape the metabolic function of autonomic neurons. Notably, recent developments in mouse genetics have enabled more detailed studies of ANS neurons and circuits, which have helped elucidate autonomic control of metabolism. Here, we will summarize the functional organization of the ANS and discuss recent updates on the roles of neural and humoral factors in the regulation of energy balance and glucose homeostasis by the ANS. Cutting-edge techniques should be harnessed to unravel how metabolism is modulated by a key part of the body’s nervous system. The autonomic nervous system (ANS) regulates many involuntary physiological processes, such as heart rate, breathing, and blood pressure. Scientists now believe that the ANS is involved in regulating metabolism, but its precise roles are unclear. Jong-Woo Sohn and Uisu Hyun at the Korea Advanced Institute of Science and Technology, Daejeon, Korea, reviewed understanding of how the ANS regulates energy balance, appetite, and glucose homeostasis. Recently-developed mouse models have provided insights into how ANS neurons translate neuronal and hormonal signals into commands during feeding, sending instructions to the liver, and mediating blood glucose levels. Several hormones have been identified that may act on a specific part of the ANS to influence appetite and metabolism. In addition, POMC neurons in the ARH reportedly regulate parasympathetic preganglionic neurons in the brainstem, which decreases insulin secretion from pancreatic β-cells4. In these examples, the activity of autonomic neurons is affected by α-melanocyte-stimulating hormone (α-MSH), a neuropeptide released from POMC neurons in the ARH, which acts on the anorectic melanocortin-4 receptor (MC4R). As such, autonomic neurons are influenced by neuropeptides and neurotransmitters8. In addition, peripheral hormones such as insulin and glucagon-like peptide-1 (GLP-1) were demonstrated to regulate the activity of autonomic neurons11. Thus, it appears that neurons of the ANS translate neural and humoral signals into commands that directly regulate peripheral organs and metabolic function. Together, these results demonstrate how the efferent (motor) divisions of the ANS regulate metabolism.The autonomic nervous system (ANS) serves as a key structure to mediate unconscious regulation of bodily function by the central nervous system (CNS). In particular, the hypothalamus utilizes the sympathetic and parasympathetic divisions of the ANS to innervate peripheral organs and to control the metabolic function of our body. For instance, anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) activate sympathetic preganglionic neurons in the spinal cord, which in turn increases thermogenesis in brown adipose tissue (BAT)13. In addition, recent studies have suggested that the gut microbiome stimulates vagal sensory neurons to affect many facets of metabolic function15. Therefore, both efferent and afferent divisions of the ANS can regulate energy balance and glucose homeostasis.However, recent evidence has demonstrated that parasympathetic or vagal afferent (sensory) fibers inform the CNS of food in the gut. For instance, it was demonstrated that ingestion of food causes mechanical stretch of the stomach or intestinal walls, which is relayed by vagal sensory neurons to the CNS and stimulates anorexigenic neurons or inhibits orexigenic (appetite-promoting) neurons to stop feedingHere, we discuss key structures of the ANS, focusing on the role of ANS neurons in the regulation of feeding and metabolism. We also summarize how neural, humoral, and other factors modulate efferent and afferent divisions of the ANS and their metabolic function.16  are located in the celiac ganglia24.The parasympathetic and sympathetic nervous systems represent the motor (efferent) part of the ANS, which innervates internal organs and regulates their function26. Paired-like homeobox 2b (Phox2b) is a transcription factor that is known to mediate the development of the parasympathetic nervous system. Thus, scientists have used Phox2b-cre mice to manipulate neurons of the parasympathetic division of the ANS26. No mouse model is currently available to selectively label sympathetic neurons.Both preganglionic and postganglionic neurons of the parasympathetic division release acetylcholine (ACh) from their terminals. Sympathetic preganglionic neurons also release ACh, but sympathetic postganglionic neurons are unique in that they use norepinephrine (NE) as the major neurotransmitter. Therefore, choline acetyltransferase (ChAT), which is a key enzyme for the synthesis of ACh, can serve as a useful chemical marker for cholinergic autonomic neurons. Using mice with Cre recombinase activity under the control of the ChAT promoter (ChAT-cre mice), researchers manipulated gene expression in a cholinergic neuron-specific manner to identify the role of specific molecules expressed by autonomic neurons23  synthesis and triglyceride (TG) secretion; impaired sympathetic function has been linked to the pathogenesis of nonalcoholic fatty liver disease (NAFLD)34. In addition, the sympathetic nervous system is an important regulator of WAT function, as evidenced by lipolysis induced by NE released from the synaptic end of sympathetic postganglionic neurons35. A recent study reported that sympathetic stimulations even lead to the browning of WAT36. The sympathetic nervous system also stimulates thermogenesis in the BAT of rodents37. In human subjects, BAT was originally known to exist only in infants, but a recent study reported that adults also have functional BAT38. These results further highlight the importance of the sympathetic nervous system as a potential target for the treatment of obesity.The ANS innervates multiple organs that regulate metabolism; the pancreas and the liver receive both sympathetic and parasympathetic innervation, whereas adipose tissues receive only sympathetic innervation23 Fig. . The par39. However, the parasympathetic nervous system has afferent fibers dedicated to sensory function. The vagal sensory neurons are bipolar neurons that project from peripheral organs to the brain stem. The somata of the vagal sensory neurons are located in the nodose ganglia (NG) -expressing NG neurons form a structure called the mucosal endings in the gut, while those of oxytocin receptor (Oxtr)-expressing NG neurons form a structure called the intestinal intraganglionic laminar endings12. Notably, optogenetic and chemogenetic activation of Oxtr-expressing NG neurons inhibited food intake, while stimulation of CGRP-expressing NG neurons had no effects. These results suggested that stimulation of a specific subpopulation of NG neurons is sufficient to inhibit feeding. Additionally, it is worthwhile to note that the right and left NGs were reported to be anatomically and functionally distinct41. Most neurons in the right NG innervate the nucleus tractus solitarius (NTS), whereas most neurons in the left NG innervate the area postrema (AP). Optogenetic stimulation of axon terminals of NG neurons, right or left, induced a significant decrease in chow intake. However, only stimulation of the right NG neuronal axon terminal resulted in place preference. These results suggested that the activity of the right NG to the NTS circuit is sufficient to induce motivated behavior. The right NG to NTS circuit was found to be connected to the dorsolateral aspect of the parabrachial nucleus (PBN), dopaminergic neurons in the midbrain, and striatum. Finally, a subpopulation of NG neurons was reported to be glucose-sensing neurons42. These glucose-sensing neurons may also suppress feeding in vivo, although this hypothesis needs to be confirmed by direct experimental evidence. The vagal sensory neurons, especially those responsible for chemical sensing, can be labeled using Nav1.8-cre mice43. This mouse model was used to identify the metabolic function of molecules expressed by vagal sensory neurons45.The sympathetic sensory fibers are intermingled with somatic sensory fibers and thus are not readily dissected anatomicallyNG) Fig. . The sti8 and AP41. The NTS, like the NG, contains many types of neurons that are also functionally heterogeneous. NTS neurons that express either cholecystokinin (CCK) or dopamine β-hydroxylase are activated by food intake, and these neurons provide excitatory input to anorexigenic CGRP-expressing PBN neurons46. CCK-expressing NTS neurons were also shown to project to the paraventricular nucleus of the hypothalamus (PVH), which is a major satiety center47. In addition, many POMC neurons in the NTS express CCK and the serotonin 2C receptor, which innervate forebrain structures to induce anorexia48. However, NTS neurons are not always anorexigenic. Tyrosine hydroxylase (TH)-expressing NTS neurons reportedly use NE as a neurotransmitter to innervate orexigenic agouti-related peptide (AgRP) neurons within the ARH, where the release of NE directly excites AgRP neurons49. Inhibition of these neurons suppressed food intake when the mice were under glucoprivic hunger, which was induced by 2-deoxyglucose. Interestingly, inhibition of TH-expressing NTS neurons failed to suppress food intake when the mice were subjected to food deprivation.As mentioned previously, vagal sensory information is transferred to neurons in the NTS12. Recently, a study demonstrated that prodynorphin (Pdyn)-expressing PBN neurons receive information regarding mechanical stretching via the NTS, which mediates anorexia and negative valence13. These results suggested that mechanical stretch induced by food in the stomach is sensed by local vagal afferent neurons and transmitted to the NTS and PBN to suppress feeding. Previous studies have suggested that vagus nerve stimulation (VNS), which was originally approved for treatment-resistant epilepsy50 and depression51, is also effective in reducing food intake54. VNS is now approved by the Food and Drug Admistration (FDA) for the treatment of obesity. Since VNS affects both the afferent and efferent arms of the vagus nerve through the application of electricity via patches attached to the skin, it is not clear how VNS can reduce food intake. Nonetheless, we envision that the central pathways involving neurons of the NTS, PBN, and possibly the hypothalamus are responsible for the anorexigenic effects.The PBN receives ascending sensory inputs from the NTS and AP55 -expressing DMV neurons60. This neural circuit was not responsible for the regulation of feeding or body weight but was involved in the maintenance of glucose homeostasis by increasing hepatic glucose production (HGP). In contrast, relatively limited data are available on the neural control of sympathetic preganglionic neurons, which is probably due to the technical difficulty of studying neural circuits in the spinal cord. It was previously shown that neurons in the hypothalamus and brainstem innervate the IML61, but the functional significance of these connections remains to be determined.Parasympathetic preganglionic neurons were previously shown to receive direct and indirect neuronal projections from several nuclei of the hypothalamus55 Fig. . Notably62. As mentioned previously, POMC neurons release α-MSH, which is a full agonist of MC4R63. Both parasympathetic and sympathetic preganglionic neurons express functional MC4Rs61. MC4Rs expressed by sympathetic preganglionic neurons were shown to increase BAT thermogenesis and blood pressure but decrease HGP26. In addition, MC4Rs expressed by parasympathetic preganglionic neurons were suggested to decrease insulin secretion26. Interestingly, patch-clamp studies demonstrated that MC4R agonists depolarize (or activate) sympathetic preganglionic neurons while hyperpolarizing (or inhibiting) parasympathetic preganglionic neurons25, which suggests that stimulations of MC4Rs increase sympathetic tone. These results at least in part explain the autonomic phenotypes observed in MC4R-deficient mice and human patients with MC4R mutations, including decreased thermogenesis, hyperinsulinemia, and resistance to obesity-induced hypertension. However, it remains unclear how MC4Rs normalize (or reduce) HGP by increasing sympathetic activity. In addition, there is currently no evidence that the activity of autonomic preganglionic neurons is modulated by α-MSH release in vivo. These remaining issues need to be resolved in future investigations. However, little is known regarding the regulation of the ANS by other neuropeptides released from hypothalamic neurons. One example is orexin (or hypocretin), which is a neuropeptide synthesized by a discrete set of neurons within the lateral hypothalamic area (LHA) to control feeding behavior and arousal64. It was previously demonstrated that LHA orexin neurons project to gut-projecting DMV neurons that putatively express orexin receptor 1/2 (OR1/2) to control gastric function66.One of the well-characterized inputs to autonomic preganglionic neurons within the DMV and IML originates from arcuate POMC neurons67. Sympathetic premotor neurons are typically found in the rostral medulla. Sympathetic premotor neurons within the rostral ventrolateral medulla (RVLM) are known to control cardiovascular functions68. In particular, MC4R-expressing RVLM neurons innervate the IML neurons that project to the lung69. Unlike the RVLM, those in the rostral medullary raphe regions reportedly regulate thermogenesis71. In particular, sympathetic premotor neurons located within the rostral part of the raphe pallidus (RPa) and raphe magnus were suggested to be involved in thermoregulation. A previous study demonstrated that optogenetic stimulation of cholinergic neurons decreased BAT thermogenesis via muscarinic M2 receptors expressed by RPa serotonergic neurons72. In another study, serotonergic neurons located in the dorsal raphe nuclei (DRN) projected to the RPa and functionally modulated BAT energy expenditure6. Given the role of DRN serotonergic neurons in regulating thermogenesis and locomotor activity74, the DRN→RPa circuit may represent an effector system to excite the sympathetic nervous system.Neurons that directly innervate sympathetic preganglionic neurons in the IML are called sympathetic premotor neurons76. Thus, peripheral hormones may have access to neurons within the NTS and DMV via the AP, which has characteristics of CVO. In the case of sympathetic preganglionic neurons, there is no nearby structure that can serve as a CVO. Therefore, sympathetic preganglionic neurons have only limited access to peripheral hormones, which may be why there are currently no data regarding humoral regulation of sympathetic preganglionic neurons. Most results regarding the role of hormones in the regulation of autonomic neurons were obtained from studies using in vivo conditional knockout mouse models and ex vivo electrophysiology experiments.Parasympathetic preganglionic neurons are also influenced by peripheral hormones, which may enter the CNS via circumventricular organs (CVOs) where the blood-brain barrier is not very tight78. Leptin is a unique fat cell-derived hormone, and many scientists have studied this hormone in the context of feeding and metabolism. Indeed, mice and human subjects lacking leptin or LepRs develop obesity, which is accompanied by decreased energy expenditure and increased food intake80. In particular, the abundant expression of LepRs by central neurons has prompted researchers to study the role of leptin in the CNS84. While deletions of LepRs in a single population of neurons failed to reproduce the obesity phenotypes observed in whole-body knockout mice86, Lowell and colleagues found that LepR deficiency in GABAergic neurons produces obesity87. These results highlighted the role of GABAergic neurons in mediating the metabolic effects of leptin, but the anatomical location of the responsible GABAergic neurons is still unknown. In the ANS, LepR deficiency in Phox2b neurons did not result in a body weight phenotype, although both food intake and energy expenditure were increased88. These results suggest that LepRs expressed by parasympathetic neurons cause changes in either food intake or energy expenditure, which is readily compensated. Multiple studies from independent groups reported that leptin applications inhibit the activity of DMV neurons via phosphoinositide 3-kinase (PI3K)-dependent activation of ATP-sensitive potassium (KATP) channels90  were first reported in the 1990s91 and that pancreas-projecting GLP-1R-expressing neurons are excited by the application of GLP-1 directly via the closure of putative K+ conductance and indirectly via GABA-activated Cl- conductance92. The excitation of DMV neurons and the increased parasympathetic tone may contribute to the well-known insulinotropic effects of GLP-1. Interestingly, by using Phox2b-cre-specific GLP-1R knockout mice, researchers reported that the conditional knockout mice show decreased food intake, glucose tolerance, and accelerated gastric emptying10. However, knockdown of GLP-1R in neurons of the NTS reportedly resulted in increased food intake in the dark cycle11.In addition to leptin and insulin, hormones released from gut endocrine cells were demonstrated to affect autonomic function. For instance, while GLP-1 is secreted largely from gut endocrine cells, GLP-1 has its cognate receptor (GLP-1 receptor or GLP-1R) throughout the brain. In particular, it was shown that DMV neurons also express GLP-1R93. CCK is released from duodenal endocrine cells in isoforms such as CCK58, CCK22, and CCK8. Neurons of the DMV express CCK receptor 1 (CCK1R), and CCK8 generates inward currents by decreasing putative K+ conductance94. Later, it was shown that CCK8 depolarizes the membrane potential of DMV neurons directly by decreasing K+ currents and indirectly by decreasing the frequency of spontaneous excitatory postsynaptic currents (sEPSCs)95. CCK1R is also expressed by neurons of the NTS96, and it was shown that in the postprandial period, c-Fos activity and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) levels are increased in CCK1R-expressing NTS neurons98. Moreover, CCK was demonstrated to activate NTS POMC neurons, which may play a role in generating satiety100. Therefore, both GLP-1 and CCK appear to affect appetite and metabolism by acting on both motor and sensory parts of the parasympathetic nervous system.Another example is CCK, which was originally identified as a gut modulator acting on vagal afferent fibersThe ANS has a major role in the control of energy balance and glucose homeostasis; sympathetic activity increases thermogenesis and hepatic gluconeogenesis, parasympathetic activity promotes insulin secretion, and vagal sensory neurons signal fullness. Therefore, it is essential to determine the mechanisms in autonomic neurons and the circuits to obtain a comprehensive understanding of whole-body metabolism in health and disease. “Conventional” autonomic neuroscience utilizes histology and electrophysiology as the major tools. Currently, findings obtained from these experiments are continuously being corroborated with findings using fine genetic tools, including mouse genetics, optogenetics, and chemogenetics. As a result, we now have more detailed information regarding autonomic control of appetite and metabolism.Given that neurons of the ANS not only regulate appetite and metabolism but also control a variety of key homeostatic functions, such as cardiac activity and breathing, it is very likely that other functions, including circulation and respiration, influence metabolism and that the ANS serves as an important mediator between these functions. For example, we need more blood and oxygen to metabolize nutrients after each meal, and the ANS likely performs fine-tuning of these homeostatic functions. Fortunately, many advancements have recently been made in other fields of neuroscience, and the cutting-edge techniques used therein could be applied to study autonomic function. However, autonomic circuitry is not as straightforward as central neural circuits since the former includes the interface between peripheral organs and peripheral/central neurons. Therefore, we need to focus on autonomic neuroscience and develop more advanced methods to investigate autonomic function and circuits. We believe that these efforts will help to gain novel insight into the autonomic function and to result in additional therapeutic options for obesity and metabolic diseases.


Throughout our lives, humans are exposed to diverse microbes that impact the development and function of our immune system. As an immense and absorptive mucosal surface exposed to the external environment, the gastrointestinal (GI) tract is a major interface in which these immunogenic interactions occur. Human subject studies have linked disruption of the intestinal bacterial community to a variety of disease conditions, and experimental models have helped us interpret these findings by elucidating mechanisms by which bacteria evoke pro- or anti-inflammatory responses through host cells and receptors. More recent studies are beginning to define the impact of nonbacterial agents in the gut such as fungi.Candida, Saccharomyces, Aspergillus, and Malassezia. However, at least some of the fungi routinely detected in the human gut are transient passengers ingested with food [The collection of fungi present in the GI tract is referred to as the gut mycobiota and can be considered part of the larger community of microbiota and meiofauna inhabitants consisting of bacteria, archaea, viruses, protozoa, and helminths. Although relatively low in abundance compared with bacteria, fungi are ubiquitous colonizers with a large role in the developmental succession of the infant microbiota . Genera ith food . Stable ith food –5.Early-life exposure to fungi is associated with reduced prevalence of wheezing and asthma later in childhood . Also, aNumerous mechanisms restrict the ability of fungi to establish invasive infections or diseases in the GI tract. In addition to Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) well known in the innate immunity field, pattern-recognition C-type lectin receptors (CLRs) play a central role in fungal recognition. CLRs Dectin-1, Dectin-2, and Mincle activate Spleen tyrosine kinase (Syk) upon binding carbohydrate polymers of the fungal cell wall such as β-glucan, mannans, and chitin, trigger signaling pathways leading to cytokine production, phagocytosis, and other effector functions. In the gut, CX3CR1+ mononuclear phagocytes (MNPs) highly express CLRs and downstream signaling mediators and, following recognition of fungi, migrate to the draining lymph nodes to induce the differentiation of naïve T cells into T helper 17 (Th17) cells and production of antifungal antibodies . Some fuLaboratory mice are broadly used for studying how the microbiota contributes to the maturation and function of the immune system. However, there is growing evidence that the limited microbial exposure experienced by laboratory mice kept in ultra-hygienic specific pathogen-free (SPF) facilities leads to a less mature immune system when compared with free-living mammals such as humans. Laboratory mice exposed to feral or pet store mice, also referred to as “dirty” mice, better recapitulate observations made in humans in models of infectious disease, colorectal cancer, and pharmaceutical interventions –17. In tAspergillus species. In addition to exhibiting hallmarks of increased lymphocyte differentiation and cytokine production, rewilded mice display a striking expansion of granulocytes, a group of myeloid lineage white blood cells such as neutrophils [Candida albicans leads to an increase in circulating granulocytes, and reducing fungal burden with the antifungal drug fluconazole leads to a corresponding decrease in granulocytes. Hence, fungi in the natural environment contribute to the composition of circulating immune cells.Laboratory mice that experience a seminatural environment through release into an outdoor enclosure facility, a process referred to as “rewilding,” display >100-fold increases in fungal burden . In thistrophils ,19. GranIt is possible that rewilded mice represent an intermediary condition of microbial exposure occupying a state in between SPF and feral mice. Rather than a binary status of “clean versus dirty” or “naïve versus exposed,” immune maturation induced by microbes likely exists in a continuum. Humans display interindividual differences in their history of infections. Incorporating mouse models with different degrees of microbial exposure including fungi may help capture some of this diversity.C. albicans are cross-reactive with airborne fungi [C. albicans strains recovered from the intestines of IBD patients display high cytotoxicity and induce greater production of the inflammatory cytokine IL-1β from macrophages compared with non-IBD isolates [C. albicans [Human Th17 cells reactive to gut-resident ne fungi , and in ne fungi ,22. Howeisolates ,24. Alteisolates . Anotheralbicans . Lastly,albicans .How the gut mycobiota influences the host may be useful to consider when attempting to model disease events in laboratory mice because intestinal fungi are generally low in abundance or undetectable by culturing methods in mice bred in SPF facilities. For example, blood neutrophil levels are lower in laboratory mice than in humans. As a major phagocyte population and first line defenders during infections, this discrepancy may confound attempts to fully utilize the mouse model to study immunity. Recent evidence highlights a previously unappreciated heterogeneity of neutrophils, especially mature neutrophils in the periphery, which may be key for their function during chronic conditions, such as cardiovascular inflammation . The divWhile colonizing laboratory mice with a genetically tractable model fungus represents an accessible reductionist approach to address these types of questions, it would be highly informative to fully characterize rewilded mice, which display alterations in abundance and composition of both the gut mycobiota and bacterial microbiota. Other experimental systems add another level of complexity by introducing viruses, which have broad effects on the mucosal immune system ,31. Know


This study examined (1) the time-varying relationship between purpose in life and perceived stress reactivity, (2) the trajectory of perceived stress reactivity as it relates to both within- and between-person purpose in life, as well as (3) the predictive utility of perceived stress reactivity and its rate of change on cognitive ability and allostatic load. The sample comprised 933 participants from the Notre Dame Study of Health & Well-being, a 10-year study of annual questionnaire packets and biennial daily diary bursts. Analyses included three-level multilevel models from which random effects were extracted and used to predict allostatic load and cognitive ability. Results indicated that individuals were affectively reactive to perceived stress, and that perceived stress reactivity declined over time. Considering the effects of purpose in life on these processes, there were two cross-level interaction effects indicating (1) more purposeful individuals were less stress reactive than less purposeful individuals, and (2) more purposeful individuals declined less in negative affect over time than less purposeful individuals. There was also preliminary evidence for a within-person interaction effect between yearly purpose in life and daily affective reactivity such that when individuals felt particularly purposeful, they also tended to be less stress reactive. Finally, higher perceived stress reactivity, as well as less decline in this construct, was predictive of better cognitive ability. These findings indicate purpose in life buffers against environmental and maturational effects on negative affect, and that perceived stress reactivity may indicate a different, more adaptive process than affective reactivity to experienced stressors.


COVID-19-associated mucormycosis (CAM) emerged as an epidemic in certain parts of the world amidst the global COVID-19 pandemic. While rhino–orbital mucormycosis was well reported during the pandemic, in the absence of routine diagnostic facilities including lower airway sampling, pulmonary mucormycosis was probably under-recognized. In this review, we have focused on the epidemiology and management of COVID-19-associated pulmonary mucormycosis (CAPM). CAPM is a deadly disease and mortality can be as high as 80% in the absence of early clinical suspicion and treatment. While histopathological examination of tissue for angio-invasion and cultures have remained gold standard for diagnosis, there is an increasing interest in molecular and serological methods to facilitate diagnosis in critically ill patients and often, immune-suppressed hosts who cannot readily undergo invasive sampling. Combined medical and surgical treatment offers more promise than standalone medical therapy. Maintaining adequate glycemic control and prudent use of steroids which can be a double-edged sword in COVID-19 patients are the key preventative measures. We would like to emphasize the urgent need for the development and validation of reliable biomarkers and molecular diagnostics to facilitate early diagnosis. The COVID-19 pandemic which started in late 2019 took the world by surprise and is still with us today. Clinically, in addition to pneumonitis and multi-organ involvement, increased susceptibility to bacterial and fungal infections is well recognized .The interplay between viral respiratory pathogens and secondary fungal infections has been of considerable interest in the last few years, especially after the emergence of influenza-associated pulmonary aspergillosis (IAPA) during the 2009 H1N1 influenza pandemic . HundredIn this review, we focus on the available literature on COVID-19-associated pulmonary mucormycosis (CAPM).Rhizopus spp., Mucor spp., Lictheimia spp., Rhizomucor spp., Cunnighamella spp., Apophysomyces spp. and Saksenaea spp. . Th. Th23]. Magnetic resonance imaging (MRI) is less useful than CT in the diagnosis of PM; however, it is more relevant for rhino–orbital–cerebral mucormycosis and it is generally helpful to identify soft tissue rather than bony abnormalities .18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) combines functional, metabolic and structural modalities of imaging and can identify areas of infection and inflammation earlier and with more sensitivity than conventional CT scan. It works on the principle that areas of infection, inflammation or malignancy have increased FDG uptake as FDG acts as a glucose analogue and is taken up by the cellular glucose transporters. The local inflammatory response and increased vascular permeability also leads to higher uptake which is reported as maximum standardized uptake value (SUV max).FDG PET/CT can be a particularly useful modality in patients with multiple risk factors for invasive fungal disease (IFD), to not only diagnose pulmonary fungal infections but also assess the extent of disease and follow up to assess residual infection status . RecentlThe demonstration of angio-invasiveness in lung tissue samples remains the corner stone in the diagnosis of PM as culture positivity rates are low. However, it is important to note that invasive tissue sampling is often delayed or not feasible due to the critical nature of the underlying illness.Direct microscopy of bronchoalveolar lavage (BAL) specimens and staining with fluorescent brighteners such as Calcofluor White and Blankophor with examination under ultraviolet (UV) light helps demonstrate broad, aseptate hyphae suggestive of the Mucorales species  23,29].,29.23,29Lung tissue can be obtained by bronchoscopic guided trans-bronchial lung biopsy (TBLB), video-assisted thoracoscopic surgery (VATS) or open lung biopsy. While TBLB is the commonest diagnostic modality to obtain a tissue specimen, VATS and open lung biopsy are useful in patients undergoing surgical management.On tissue specimens, Hematoxylin and Eosin (HE), Grocott Methanamine Stain (GMS) and Periodic Acid Schiff base (PAS) stains are used to demonstrate the fungal hyphae. Presence of broad (5–20 μm), irregular, ribbon like, aseptate or pauciseptate, wide angle branching hyphae are characteristic of Mucorales and should be differentiated from septate, narrow angle hyphae in aspergillosis. However, septations and angle of branching may be affected by tissue processing. Tissue samples may also show evidence of angioinvasion, necrosis, hemorrhagic infarction and neutrophilic infiltration (in non-neutropenic hosts). Chronic lesions may be pyogranulomatous with Splendore Hoeppli phenomenon  . PCRs onFungal cultures have only 40–50% positivity rates even when histopathology shows fungal hyphae and are usually positive by day 2 to 7 ,30. MatrMucorales sp. in 66 culture isolates and noted that amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species [Mucor, esp M. circinelloides and Cunninghamella strains. Mucor species were more resistant to azoles than Rhizopus species.Anti-fungal susceptibility testing is particularly useful in cases of treatment failure and also for epidemiological purposes. Lack of well-established clinical breakpoints remains a major limiting factor for routine testing ,30. Vita species . PosaconIn a recent systematic review by Jeong et al., histopathology aided the diagnosis in 97%, cultures were positive in 78%. Genus and species-level identification was possible by morphological methods only in 53% and molecular methods were found to be promising .Molecular detection of Mucorales DNA is generally used as an adjunctive method to histopathology, culture and microscopy for identification of Mucorales on culture isolates and tissue specimens. Fresh tissue specimens are preferred to formalin-fixed tissue specimens as more DNA can be extracted from the former . The tar®  has been clinically evaluated in severely immunosuppressed patients with proven/probable PM as per EORTC-MSG criteria. This assay targets the 18s rDNA region of Mucor sp., Rhizopus sp., Rhizomucor sp. and Cunnighamella sp., without genus discrimination and had a sensitivity of 100% and specificity of 97.9%. They recorded a culture positivity rate of 3.1% compared to PCR positivity of 8.5%. MucorGenius® PCR assay also picked up 10 possible cases of mucormycosis, all of which were culture negative [Mucorales DNA can be detected using PCR assays on clinical specimens including BAL samples, blood and urine. The commercially available pan-Mucorales real-time PCR assay MucorGeniusnegative .While PCR-based methods can lead to rapid and early diagnosis, the issue lies with lack of standardization and clinical evaluation of assays . Hence, (i)Biomarkers: The current biomarkers for IFD like serum  beta-D-glucan assay (BDG) and serum and BAL Galactomannan do not detect mucormycosis as the cell wall of Mucorales species lack galactomannan and beta-D-glucan. (ii)There are no currently available serological tests for mucormycosis, though enzyme-linked immunosorbent assays, immunoblots and immunodiffusion tests have been evaluated with variable success previously ,35.(iii)Mucorales-specific T cells: These have been studied in hematologic patients and need further validation in other populations. Potenza et al. have demonstrated the use of Mucorales-specific T cells as a surrogate diagnostic marker in hematologic patients in whom early an diagnostic biopsy is often challenging to perform . In a smThe common clinical and diagnostic features that lead to suspicion of pulmonary mucormycosis in COVID patients are listed in CAPM is treated in keeping in lines with non-COVID-19 associated mucormycosis. The first line agent as per the European Confederation of Medical Mycology (ECMM) 2019 guideline for treating mucormycosis is liposomal amphotericin B, usually administered at a dosage of 5 mg/kg/day . Doses uPosaconazole and isavuconazole are the only effective azole agents active against mucormycosis. They can be used as less preferred alternatives to amphotericin B in first line therapy and also for salvage therapy . The oraIn a small single arm open label trial, isavuconazole has shown similar efficacy compared to amphotericin B for the primary treatment of mucormycosis . IsavucoTreatment with amphotericin B is continued until clinical resolution and patients are then stepped down to oral posaconazole or isavuconazole, which is continued until radiological resolution and complete reversal of immunosuppression .Combination therapy with posaconazole or echinocandins (caspofungin) with lipid formulation amphotericin B backbone have shown some in vitro efficacy but there is poor clinical data to support routine use . CombinaThere is data emphasizing the combination of surgical debridement with systemic anti-fungal therapy leading to better outcomes as compared to anti-fungal therapy alone .Surgery should always be considered in patients with CAPM, though in some patients there might be issues with technical difficulties due to involvement of large vessels or mediastinal structures or in very sick patients with multiple co-morbidities. Surgery either in the form of resection, lobectomy or pneumonectomy improves survival when combined with appropriate medical therapy ,49. SurgApart from a small study which showed reduced incidence of CAPA in the prophylaxis arm but no survival benefit, no concrete evidence exists which investigates the use of anti-mold prophylaxis in COVID-19 ICUs. However, considering the emergence of multi-drug resistant fungal pathogens, nebulized formulations of amphotericin B may be worth considering; this modality is used in the post-lung transplant setting and also recommended as an alternative to posaconazole in high risk haematology–oncology patients .Mortality is high in the absence of early initiation of anti-fungal therapy with surgical management and reported in various studies ranging from 73–88% . The pooMaintaining strict glycemic control and adhering to a protocol-based use of systemic steroids has been shown to prevent COVD-19-associated mucormycosis . Anti-miHigh environmental spore count and contaminated humidifier water and oxygen supplies may have contributed to the high disease burden of CAM in India ,56,58.Implementing strict protocols for sterilization and disinfection of shared equipment, ensuring infection control requirements are adequately maintained during construction activities, proper maintenance of ventilation systems and surveillance are important to prevent hospital outbreaks .CAPM is a well-recognized, lethal yet treatable complication of COVID-19 pneumonitis. Overall, there is a paucity of published data on CAPM and one important recommendation is to encourage the recording and reporting of cases via international registries  who need to play an important part in increasing awareness as well as co-ordinating and recruiting for research studies. The potential for learning from each other cannot be over emphasized. Clinicians need to develop a high index of suspicion for CAPM and promoting enhanced surveillance for co-infections, including Mucor, as a part of routine clinical practice is essential.Early diagnosis leading to appropriate and timely intervention is crucial for determining the overall outcome of patients with CAPM. The absence of a biomarker makes early diagnosis very challenging and yet is an important goal if we are to alter the prognosis of this deadly disease. This is an area where collaborative working is required between industry and clinicians to ensure appropriately designed studies are conducted leading to the provision of prognostic-altering diagnostic and therapeutic solutions. A combined co-ordinated approach can do much to improve patient outcomes from this under recognized devastating complication of COVID-19.


Open repair of thoracoabdominal aortic aneurysm (TAAA) in a patient with severe aorto-iliac occlusive disease is considered to cause an extremely high risk for spinal cord injury. A 71-year-old man who had previously undergone axillo-bifemoral bypass for aorto-iliac occlusive disease presented with persistent dilation of a TAAA. Using distal perfusion via partial extracorporeal circulation at mild hypothermia, we performed segmental sequential repair of Crawford type II TAAA. Various efforts were made to avoid spinal cord injury and ischemic visceral organ damage. Consequently, the patient completely recovered without any serious complications. Among serious complications after repair of TAAA, spinal cord injury (SCI) is one of the most devastating. A great number of factors have been demonstrated to be associated with the development of SCI after the operation, including coronary artery disease, renal insufficiency, and the extent of TAAA repair in the severely atherosclerotic aorta. Particularly, TAAA patients with severe aorto-iliac occlusive disease (AIOD) are at high risk of paraplegia because of occlusion of the infrarenal abdominal aorta and its branches, including the lumbar and internal iliac arteries, which play an important role in distal spinal cord perfusion. We report the case of a patient with AIOD who successfully underwent surgery for TAAA without SCI, as well as strategies toward avoiding SCI and ischemic visceral organ damage during the operation.Open surgical repair of thoracoabdominal aortic aneurysm (TAAA) is one of the most challenging cardiovascular procedures as it continues to be associated with high morbidity and mortality.A 71-year-old man with AIOD underwent aorto-bifemoral bypass 12 years before presentation. Nine years earlier, the left leg of this graft was occluded, and a femoro-femoral (F-F) bypass was performed. Six years earlier, the graft reoccluded. Thus, axillo-bifemoral (Ax-biF) bypass and left femoropopliteal bypass were performed, and these grafts have remained patent to date. Five years ago, the patient underwent a total arch replacement for a distal true arch aneurysm (maximum diameter of 60 mm) using the elephant trunk technique, along with coronary artery bypass grafting of the right posterior descending artery  were recorded throughout the operation.The entire thoracoabdominal aorta was exposed via the left fourth intercostal space, and a retroperitoneal approach was undertaken , moderate systemic heparinization (1.0 mg/kg), and mild permissive hypothermia . After p-ECC was started, the descending aorta was clamped at the level of the 11th ICA, and the suprarenal portion of the abdominal aorta was opened. The celiac artery was occluded; thus, both the renal arteries (RA) and superior mesenteric artery (SMA) were perfused using 8-Fr balloon-tipped catheters via a separate single roller pump at the arterial flow. Before these procedures, we connected one of the divided arterial cannulas directly to the distal side of a 22 mm Gelweave Coselli thoracoabdominal graft with four 8 mm diameter side branches  using an I-shaped connector to perfuse the visceral artery quickly after each anastomosis. The right RA, SMA, and left RA were anastomosed one by one to the side branches of the Coselli graft with 5-0 polypropylene, using the Carrel patch method. Then, the aortic cross-clamp site was changed just below the 10th ICA, and the origin of the 11th ICA was anastomosed to the remaining branch of the Coselli graft using the inclusion technique. To reconstruct the remaining descending aorta and the 10th ICA, a 22 mm woven J-graft Shield neo with one 9 mm branch  was anastomosed to the proximal end of the Coselli graft. Aortic cross-clamping was moved to a level below the sixth ICA, the remaining aneurysm was opened, and the 10th ICA was reconstructed to the side branch of the J-graft. During this anastomosis, the 10th ICA was perfused directly through the SPF catheter, using a silicone balloon  with the inner pressure of the coronary perfusion circuit of 300 mmHg  on the third postoperative day and decreased gradually to 2.50 mg/dL at discharge. Hemodiafiltration was not performed after the surgery. It is useful to know the precise level of the origin of the AKA before reconstruction of the intercostal arteries. We determined AKA levels via preoperative enhanced CT and intraoperative clamp test of the intercostal arteries with MEP monitoring. The cerebrospinal fluid drainage tube was inserted the day before the operation. Postoperatively, hemoglobin was increased above 10 g/dL by blood transfusion, and mean blood pressure was maintained above 80 mmHg for 3 days.To avoid SCI, various efforts have been made routinely in our hospital, even as per previous studies. reported that an open proximal anastomosis under deep hypothermic circulation arrest (DHCA) might offer superior spinal cord protection to the arch clamping technique during repair of DTAA/TAAAs involving the distal arch. However, the routine use of DHCA for DTAA/TAAA repairs is controversial because of cerebral ischemia due to hypotension during the cooling and rewarming periods and because of the limitation of myocardial protection, which causes postoperative low cardiac output syndrome. Moreover, because DHCA requires a longer cardiopulmonary bypass time, it causes lung dysfunction after the operation and severe coagulopathy, which may increase the risk of serious surgical bleeding. When aortic cross-clamping can be safely performed via preoperative enhanced CT and intraoperative direct epiaortic ultrasound, we prefer a physiologic arch clamping technique using p-ECC with a beating heart at mild hypothermia.Kouchoukos and colleaguesTAAA repair procedures for AIOD patients are not only at high risk of paraplegia due to the lack of distal spinal cord perfusion but they are also exposed to the highly complicated procedure of establishing p-ECC. In this situation, maintaining the flow balance between venous drainage and arterial reinfusion by femoral return cannulation is challenging. Severe general hypotension is easily induced, especially during the starting period of p-ECC and massive intraoperative bleeding. In this case, the preexisting Ax-biF bypass was patent, and we used this graft as an arterial return cannula (In this case, we expected that we could not obtain sufficient blood flow to the visceral organs from the collateral channels during distal perfusion from the p-ECC during aortic cross-clamping. To reduce the ischemic time of the visceral organs, we performed distal anastomosis first (A 71-year-old high-risk patient with a history of Ax-biF bypass for AIOD successfully underwent operative graft replacement for an extended type II TAAA. We described very effective techniques to prevent ischemia of the visceral organs and spinal cord that were used in this case.