Our results show that fish hydrolysate supplementation prevented the observed stress-induced dysregulation of proteins relative to mitochondrial pathways and the neuronal network. These findings suggest that fish hydrolysate represents an innovative strategy to prevent the adverse effects of stress and participate in stress management.Over the past several decades, stress has dramatically increased in occidental societies. The use of natural resources, such as fish hydrolysates, may be an attractive strategy to improve stress management. Our previous study demonstrated the anxiolytic effects of fish hydrolysate supplementation in mice exposed to acute mild stress by limiting stress-induced corticosterone release and modulating the expression of a number of stress-responsive genes. Here, we explore hippocampal protein modulation induced by fish hydrolysate supplementation in mice submitted to acute mild stress, with the aim of better elucidating the underlying mechanisms. Hippocampi from the same cohort of Balb/c mice supplemented with fish hydrolysate (300 mg·kg Stress has dramatically increased in occidental societies over the past several decades . Stress The use of natural resources, such as fish hydrolysates, may be an attractive strategy to improve stress management. They are generally produced from fish by-products, thus minimizing the economic and environmental cost . Protein−1) on stress responsiveness , flavoprotein 3 (Ndufv3), and ATP synthase F(0) complex subunit B1 (Atp5pb). In our previous study, we highlighted an interaction between supplementation and stress for the mitochondrial genes ATP8, ATP6, and COX1 . MitochoFish hydrolysate supplementation downregulated several proteins involved in the neuronal network, e.g., nesprin-1 (Syne 1), neuronal calcium sensor 1 (Ncs1), glycogen synthase kinase-3 beta (Gsk3b), and kalirin (Klrn). Interestingly, these proteins all contribute to the integrative organization of the neuronal network. Nesprin-1 (Syne 1) has been shown to play critical roles in neurogenesis and neuronal migration in mice . NeuronaMost of these proteins are also key factors in the regulation of the DA pathway. Ncs1 has been found to regulate the phosphorylation, trafficking, and signaling profile of the receptor of type 2 dopaminergic neurons (D2R) . DA reguOverall, those results suggest that fish hydrolysate supplementation could prevent the deleterious effects of acute mild stress by modulating the DA pathway. However, the interaction between fish hydrolysate and the DA pathway requires further investigation.Finally, our previous study showed that the expression of Per2, one of the most important circadian rhythm genes, was increased by stress and supplementation in the hippocampus . Here, wOur study had several limitations. An acute mild stress protocol and short supplementation period  undoubtedly induced limited modulation of protein expression in the hippocampus. The high sensitivity of the mass spectrometer used for our proteomics analyses allowed us to analyze several low-copy number differential proteins, resulting, however, in a moderate enrichment in GO terms with sometimes few implicated proteins. Thus, obtained results would require further validation on an independent cohort. Likewise, chronic stress models with longer supplementation periods should confirm the mechanisms underlying the better reactivity to stress induced by fish hydrolysate supplementation assessed in this study and eventually provide additional insights into other molecular mechanisms. A complementary metabolomics approach could be relevant for further validating the role of fish hydrolysate in regulating stress by demonstrating its involvement in pathways related to metabolic processes. Finally, characterization of the peptides from fish hydrolysate responsible for its anxiolytic-like activity is ongoing in our laboratory.In this study, we applied label-free quantitative proteomics analysis to obtain a comprehensive picture of the mouse hippocampal response to acute mild stress after fish hydrolysate supplementation. Our results demonstrate that fish hydrolysate rescues the adverse effects of mild stress by regulating mitochondrial pathways and the neuronal network, which are essential for stress management. Fish hydrolysate appears to be an innovative strategy to regulate and manage stress. Moreover, fish hydrolysate may modulate circadian rhythms. Complementary studies are required to reinforce these preliminary data and investigate the role of fish hydrolysate in diseases associated with aging, such as neurodegenerative diseases, which are tightly associated with alterations in the circadian rhythms.


Late recovery of consciousness following intensive care unit treatment of COVID-19 is a frequent and puzzling phenomenon. Many of these patients showed no signs of structural brain injuries and enjoyed full cognitive function prior to their illnesses. Prolonged coma and recovery accompanied with hypoxia and markedly reduced brain metabolism are also present in certain patients after cardiac arrest and certain vertebrate animals like the painted turtle. The latter have evolved specialized physiological processes to preserve brain function during prolonged coma linked to loss of oxygenation. We postulate the existence of a protective down-regulated state in specific clinical scenarios in humans similar to that observed in anoxia-tolerant vertebrates. Induction of this state suggests new approaches to enhancing coma recovery. The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cognitive and motor functions after prolonged delays. A common electroencephalogram (EEG) signature seen in these patients is burst suppression [8]. Biophysical modeling has shown that burst suppression is likely a signature of a neurometabolic state that preserves basic cellular function “during states of lowered energy availability.” These states likely act as a brain protective mechanism [9]. Similar EEG patterns are observed in the anoxia resistant painted turtle [24]. We present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. We begin with the Ching model and integrate findings from other clinical scenarios and studies of the anoxia-tolerant physiology of the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injury to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. This putative protective down-regulated state appears similar to that observed in the painted turtle and suggests new approaches to enhancing coma recovery [12]. Treatment for severe COVID-19 has required weeks, and in some cases months, of mechanical ventilation using multiple anesthetic regimes . In prinThe prolonged recovery of consciousness seen in some COVID-19 patients has multiple contributing factors. There is a severe oxygenation problem produced by an acute respiratory distress syndrome (ARDS) . Indeed,Few clinical scenarios are comparable to COVID-19. A possible exception is a recent study of patients remaining unconscious for 3–6 wk following post-cardiac arrest coma with limited or minimal evidence of structural brain injury . A commoA simple biophysical model has been proposed that offers a metabolic mechanism to explain burst suppression . It is hWe present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. Our analysis begins with the Ching model and integrates findings from other clinical scenarios and studies of anoxia-tolerant vertebrates, such as the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injuries to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. These mechanisms could be analogous to a protective down-regulated state (PDS) observed in anoxia-tolerant vertebrates , 13.Burst suppression is a well-known EEG pattern during which isoelectric (flat) periods alternate with active periods . This pa2). For hypoxic brain injuries and hypothermia, there is likely a direct effect on cerebral metabolism linked to reduced synaptic activity resulting from impaired neuronal and mitochondrial function. For the GABAergic anesthetics—propofol, the barbiturates, and the inhaled ethers—the decrease in CMRO2 is likely mediated through direct inhibition of adenosine triphosphate (ATP) synthesis and blocking of the respiratory chain within the mitochondria  in the ATP production rate represents a decrease (increase) in CMRO2. The key feature of this system is that a decrease in ATP yields increases in potassium conductance and outward potassium currents due to inability to maintain the sodium-potassium-ATP-dependent pumps. Hence, neuronal membranes hyperpolarize, spiking activity shuts down, and the onset of the suppression period begins. The duration of the suppression period is proportional to the decrease in ATP, the free variable in this model. At the point where the potassium conductance reaches a maximum, ATP begins to recover, the potassium leak current terminates, the suppression period terminates, and the burst activity returns.Ching and colleagues  developeThe Ching model without the metabolic component was specifically designed to produce the alpha oscillations (8–12 Hz) that are typically observed during unconsciousness maintained by GABAergic anesthetics , 20. The2, and thereby, contributing to a neuroprotective state (Forgacs and colleagues  used theve state . Hence, ve state  supportsThe Ching model for burst suppression provides a general mechanism for slowing  or shutt∘C, the turtle can withstand 48 h of anoxia, whereas for temperatures near 1∘ to 3 ∘C, the animal can withstand 5 mo of persistent anoxia. Following reoxygenation, normal neuronal function returns within hours (An EEG pattern that is almost identical to trace alternant has been observed in the painted turtle, perhaps nature’s most anoxia-resistant vertebrate . During in hours . During in hours . A key min hours . After 2in hours . This GAin hours , most ceTo explain brain adaptations to hypoxia/anoxia and hypothermia in anoxia tolerant vertebrates, Hochacka and Guppy  proposed28The frequent hypoxia characteristic of COVID-19 patients likely contributes to neuronal injury rather than cell death . For exa5As noted, certain vertebrate species, like the painted turtle, have evolved neuroprotective mechanisms to withstand extended periods of metabolic stress –44. ThesWe propose that hypoxia combined with certain therapeutic maneuvers , 43–46 m435The key common factor in establishing a PDS in vertebrates is deep global suppression of cerebral metabolism , 48 initUse of hypothermia as a therapy following cardiac arrest  likely pIf prolonged recovery of consciousness in COVID-19 patients does reflect a human PDS, several measurements may be informative. First, in other vertebrates, changes in excitatory and inhibitory neurotransmitters and receptors occur immediately in response to hypoxia associated with the spike arrest phase of the PDS response , 55. Ta Second, If a human PDS underlies prolonged recovery of consciousness in severe COVID-19 patients, we propose a two -part strategy to promote emergence . In all 61As a second part, pharmacological agents used to treat cognitive impairment following disorders of consciousness , 34, 66 7169The natural history of recovery of consciousness of COVID-19 patients after ICU care is being documented. Our analysis predicts the existence of a human form of PDS that may underlie prolonged recovery of consciousness following treatment for severe COVID-19 or treatment for post-cardiac arrest treated with hypothermia. The possible existence of a human PDS suggests many testable hypotheses for further investigation and the possibility of developing novel therapeutic strategies. These directions should be guided by the elements of successful rescue of human brains from pathological states and the recovery of other vertebrate brains from extreme conditions. The putative human form of PDS suggests that negative prognostic conclusions should be strictly avoided in any patients without brain injuries, independent of duration of impaired consciousness , 5, 8.


The most common treatment of spontaneous tumor rupture hemorrhage (STRH) is transcatheter arterial embolization (TAE) followed by liver resection, and surgical navigation using near-infrared fluorescence is effective method for detecting hidden lesions and ill-defined tumor boundaries. However, due to the blockage of the tumor-supplying artery after effective TAE treatment, it is difficult to deliver sufficient fluorescent probes to the tumor region. In this study, we report on the successful application of superstable homogeneous intermixed formulation technology (SHIFT) in precise conversion hepatectomy for ruptured hepatocellular carcinoma (HCC). A homogeneous lipiodol–ICG formulation obtained by SHIFT (SHIFT-ICG) was developed for clinical practice for STRH. A ruptured HCC patient received the combined protocol for embolization and fluorescence surgical navigation and exhibited excellent hemostatic effect. Lipiodol and ICG were both effectively deposited in the primary lesion, including a small metastatic lesion. In follow-up laparoscopic hepatectomy, SHIFT-ICG could clearly and precisely image the full tumor regions and boundaries in real time, and even indistinguishable satellite lesions still expressed a remarkable fluorescence intensity. In conclusion, the simple and green SHIFT-ICG formulation can be effectively used in emergency embolization hemostasis and later precise fluorescence navigation hepatectomy in patients with ruptured HCC bleeding and has high clinical application value.  Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is a significant cause of cancer-related mortality . The preA promising method for this situation is fluorescent surgical navigation. Indocyanine green (ICG) is the most commonly used clinical fluorescent imaging agent. In recent studies, ICG has become increasingly important in identifying HCC during hepatectomy , 9. HoweTo deal with this issue, we presented a technique called ‘superstable homogeneous intermixed formulation technology’ (SHIFT) for the homogeneous physical mixing of a lipiodol and ICG formulation . The SHIFT-ICG is very suitable for fluorescence-navigated liver resection following long-term TAE conversion . This stJiangsu Hengrui Pharmaceutical Co., Ltd  provided the lipiodol. Dandong Medical and Pharmaceutical Co., Ltd  supplied indocyanine green for the study. Oil red O was purchased from Wuhan Servicebio Biotechnology Co., Ltd .2) reached a supercritical state [in vitro.First, 10 mg ICG and 10 ml lipiodol were added to the clean reactor of SHIFT developed by our group. Second, the reaction pressure was set at 20 MPa, temperature at 35°C and stirring speed at 1000 rpm. In this state, carbon dioxide  was used for observing the suspicious sites in advance of tumor resection with the camera's head 10–20 cm away. After resection of the lesion, the FLS was used to examine whether fluorescence remained in the resected site or surgical specimens. After resection, all specimens were pathologically examined.Research procedures involving humans were conducted under the ethical guidelines of the institution and the national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. North Sichuan Medical College's Institutional Review Board approved this study and registered it with the Chinese Clinical Trial Registry, and the registration number is ChiCTR2000035055.in vivo studies about fluorescence surgery after long-term TAE conversion therapy.Conventional drug dispersion in interventional therapy is achieved by a three-way stopcock, and the unstable drug dispersion has always been a key factor that restricts the clinical prognosis. Considering the good solubility of supercritical carbon dioxide, we reported a superstable homogeneous iodinated formulation technology. In this study, a conventional three-way stopcock was used as a control (the MIX group). As shown in 2 located in segment VIII  scan showed abdominal cavity effusion  and a soent VIII  with rupent VIII . Subsequin vitro tumor specimens  again at 1 and 4 weeks after the surgery to prevent liver failure caused by residual liver insufficiency . Three mThe long-term oncological outcome should be considered in managing ruptured HCC in addition to acute-phase management dealing with bleeding issues. The management approach comprises two steps, TAE and surgical resection, to achieve hemostasis and stabilization of the patient first and then to complete the treatment with oncological surgery , 16. HowAs a safe reagent, ICG is used in clinical practice to assess hepatobiliary function, liver and gastric blood flow and cardiac output, among other things. Fluorescence imaging of ICG for the detection of HCC or metastases has been widely demonstrated , 19. HowTherefore, we proposed a fluorescence surgery navigation strategy after long-term TAE conversion therapy using fluorescent probe and lipiodol formulation. However, to achieve this goal, the first problem to solve was that hydrophilic ICG drugs cannot disperse in oily substances , 23. In The simple and green SHIFT-ICG formulation, with excellent embolism and fluorescence imaging performance, can be effectively used in emergency embolization hemostasis and later precise fluorescence navigation hepatectomy in patients with ruptured HCC bleeding and has high clinical application value.


Dear Editor,Advances in multiple myeloma (MM) therapies have enhanced the likelihood of achieving deep and durable treatment responses which carry significant prognostic implications. Obtaining a complete response (CR) is an independent predictor of longer progression-free survival (PFS) and overall survival (OS) in MM –3; howev−6, and only 37% reported using MRD status to guide decision making [how and when MRD might influence their management. Moreover, it was conducted in the months leading up to and just after the FDA approval of the clonoSEQ next generation sequencing assay for MRD [In a previous survey of clinician attitudes and practices toward MRD in MM, we found that in a respondent pool enriched for academic clinicians 91% reported assessing for MRD, 50% using an assay with a sensitivity threshold <10n making . This suIn this study, we surveyed MM clinicians to understand their general attitudes toward MRD in MM and then if/how MRD status might impact their decision making using certain common clinical scenarios. We hypothesized that there would be a discrepancy between how respondents said they felt about using MRD to guide decision making in MM and how they responded to specific clinical scenarios.Post-induction therapy, standard-risk, transplant-eligible, MRD negativePost-induction therapy, standard-risk, transplant-ineligible, MRD negativePost-transplant, standard-risk, MRD positiveDuring maintenance therapy, standard-risk, sustained MRD negativeDuring maintenance therapy, standard-risk, MRD positiveAn anonymous internet survey was distributed primarily through Twitter between November 2020 and December 2021 with the use of registered cancer ontology tags #mmsm and #mmMRD. The survey tool was approved by the institutional review board at the University of Chicago (supplement). In brief, the clinical scenarios for newly diagnosed MM included the following:For each scenario, respondents reported if and how their answer would be different based on changes in disease risk  or MRD status.There was a total of 90 respondents who agreed to participate; 89 (99%) completed the core survey, of which 68 (76%) submitted responses to the optional clinical scenarios section. Self-identified academic clinicians made up 76% of respondents (68/89) as opposed to a private practice or hybrid setting 21/89, 24%). Median clinical experience was 10 years as a hematologist/oncologist and 20 patients with MM per week  for not using MRD were: inability to order MRD (22%), unclear when to assess for MRD (22%), lack of actionability 19%), and cost (16%)  to the clinical scenarios previously discussed . That 60% of respondents reported using MRD status to guide decision making is surprising, considering that many of these respondents expressed a concern over the lack of data to use MRD status in this manner. This discrepancy points to an interesting phenomenon of the ‘insidious’/subconscious influence that MRD status has on decision making. It is also notable that the percentage of those using MRD to guide decision making rose from the 37% we reported in an earlier iteration of this survey [Analysis of responses to the clinical scenarios in aggregate reveal that 53/68 (78%) individual respondents would change at least one decision based on the presence of high-risk vs standard-risk disease, in favor of intensifying or continuing treatment in high-risk disease. A total of 41/68 (60%) individual respondents would change at least one decision based on an MRD result, and 37/68 (54%) used both disease risk and MRD status to make decisions. Importantly, of the 50 participants who responded that there is no data for MRD status to guide decision making, 27 (54%) ultimately answered a clinical scenario Interestingly, MRD status led to decisions being made in a bidirectional fashion. MRD positivity led to clinicians seeking to intensify therapy, while MRD negativity led to de-escalation of therapy; this includes a strong preference for discontinuation of maintenance therapy in those with sustained MRD negativity and standard-risk disease.Limitations of this study include a small sample size with the majority being academic clinicians, which may lean toward a higher propensity for usage of MRD testing in MM. The survey was primarily distributed by Twitter, making tracking of the survey response rate difficult to assess. Not all clinicians who treat myeloma are active on Twitter, so we cannot say whether our respondents were representative of the entire myeloma clinician community. This survey only covered scenarios involving newly diagnosed MM and is not exhaustive of every possible clinical decision point. The nuances in the clinical management of MM cannot be properly conveyed in such a survey.The merits of whether MRD status should be used to guide decision making in MM remain hotly debated, especially considering that over half of respondents stated there is no data to support this strategy. The results of this survey suggest that MRD status is in fact subtly influencing decisions and serve as a catalyst for further investigation of MRD-guided treatment strategies in MM. There has thus far been only retrospective evidence that making clinical decisions based on MRD may improve outcomes . Two triComplete Survey


Leaded fuel used by piston-engine aircraft is the largest source of airborne lead emissions in the United States. Previous studies have found higher blood lead levels in children living near airports where leaded aviation fuel is used. However, little is known about the health effects on adults. This study is the first to examine the association between exposure to aircraft operations that use leaded aviation fuel and adult cardiovascular mortality. We estimated the association between annual piston-engine air traffic and cardiovascular mortality among adults age 65 and older near 40 North Carolina airports during 2000 to 2017. We used several strategies to minimize the potential for bias due to omitted variables and confounding from other health hazards at airports, including coarsened exact matching, location-specific intercepts, and adjustment for jet-engine and other air traffic that does not use leaded fuel. Our findings are mixed but suggestive of adverse effects. We found higher rates of cardiovascular mortality within a few kilometers downwind of single- and multi-runway airports, though these results are not always statistically significant. We also found significantly higher cardiovascular mortality rates within a few kilometers and downwind of single-runway airports in years with more piston-engine air traffic. We did not consistently find a statistically significant association between cardiovascular mortality rates and piston-engine air traffic near multi-runway airports, where there was greater uncertainty in our measure of the distance between populations and aviation exposures. These results suggest that (i) reducing lead emissions from aviation could yield health benefits for adults, and (ii) more refined data are needed to obtain more precise estimates of these benefits. Subject Areas: Toxic Substances, Health, Epidemiology, Air Pollution, Ambient Air Quality. JEL codes: Q53, I18. Lead is a neurotoxin that damages multiple systems in the body. While neurodevelopmental effects in children are well documented, adults are also adversely affected by lead exposure . Of partPiston-engine aircraft operations using leaded fuel  currently represent the largest source of airborne lead in the U.S., contributing 70% of lead emissions . While jThe United States Environmental Protection Agency (EPA) estimates that over 5 million people live in census blocks located within 500 m of a runway at an airport with piston-engine aircraft ,7,8. TheWe addressed this gap in the literature by estimating the effects of proximity to airports and of year-to-year changes in piston-engine and general aviation aircraft operations on cardiovascular mortality rates among older adults from 2000 to 2017 in North Carolina. Our study used a quasi-experimental research design that examined the association between piston-engine operations and annual cardiovascular mortality rates among individuals age 65 and older living in census block groups closer to airports (the “treated” group) and farther away from airports (the “control” group). We used coarsened exact matching  to ensurOur findings were mixed. We found higher cardiovascular mortality rates within a few kilometers downwind of single- and multi-runway airports, though these results were not always statistically significant. We also found higher cardiovascular mortality rates near single-runway airports in years with more piston-engine air traffic. The magnitude of this association declined monotonically from 1 km to 3 km from airport runways. This adverse effect was even more pronounced within 1 km downwind of single-runway airports. However, we did not find consistent statistically significant adverse effects from changes in annual piston-engine operations near multi-runway airports, where there was greater uncertainty about which runways and block groups experienced exposures to leaded fuel emissions. The statistically significant adverse effects were also limited to Instrument Flight Rules (IFR) piston-engine flights, which are explicitly tracked by FAA computer systems. We did not find statistically significant adverse effects for general aviation flights for which the FAA data were less reliable.Tetraethyl lead is added to aviation gasoline to boost octane and prevent engine knock. Since the 1970s, piston-engine aircraft have predominantly used a grade of avgas called one hundred octane low lead (100LL) containing 2.12 g of lead per gallon . AlternaPiston-engine aircraft lead emissions occur throughout the phases of a flight, including start-up, idling, taxiing, run-up, takeoff, cruising, and landing. Lead emissions are highly concentrated during ground-based run-up operations conducted prior to takeoff, next to the end of the runway, making this area the maximum impact site for lead air concentrations at airports . Release3, with the range in concentrations largely explained by monitor location relative to the end of the runway. Monitoring values exceeded the National Ambient Air Quality Standard (NAAQS) for lead of 0.15 µg/m3 over a rolling three-month average at two of the airports. In 2020, the EPA extrapolated air quality modeling results to estimate three-month average lead concentrations at U.S. airports nationwide and found that they ranged from 0.0075 µg/m3 to 0.475 µg/m3 at the maximum impact site and up to 500 m downwind [EPA has discussed considerations in the determination of whether aircraft lead emissions endanger public health or welfare but has not yet issued a proposed determination evaluating endangerment . In 2008Previous studies have examined the effect of exposure to aviation fuel on children’s blood lead levels. A study of six counties in North Carolina found higher BLLs among children living within 1.5 km of airport boundaries after controlling for other lead exposure risk factors including socioeconomic status and housing age . A studyWe are aware of only one peer-reviewed study examining occupational exposure to lead from avgas. A study of aircraft maintenance workers in the Republic of Korea found significantly higher BLLs among maintenance crews at air bases where leaded avgas was used compared to air bases where jet fuel was used . WorkersEmpirical studies have also shown increases in air and soil lead levels near airports. Carr et al.’s study of Santa Monica Airport found air lead concentrations above background levels within 450 m of the airport boundaries when averaging over a rolling three-month period and up to 900 m downwind of the airport on individual days . A studyThe EPA’s Integrated Science Assessment for Lead found robust evidence of a causal relationship between lead exposure and coronary heart disease and hypertension in adults . Lead afThe EPA noted that there is uncertainty about the timing, frequency, and duration of lead exposure causing adverse cardiovascular effects . BecauseWhile we are unaware of existing research on the impact of leaded aviation fuel on cardiovascular health, several studies have examined the health effects of aviation noise and other pollutants. A study of 89 major U.S. airports found that hospitalization for cardiovascular disease was significantly associated with modeled zip-code aircraft noise . StudiesStudies have also examined whether populations living near airports have different sociodemographic characteristics than those living farther away. EPA’s analysis of populations living within 500 m of airports nationwide found, on average, a higher proportion of White residents, a lower proportion of residents of color, and a slightly lower proportion of children eligible for free or reduced-price lunch near airports compared to the total U.S. population . A workiWe compiled a comprehensive statewide panel dataset of cardiovascular mortality rates in North Carolina from 2000 to 2017. Like other studies ,28, we fn = 1,436,194). The mortality records included the individual’s date of birth, date of death, residential address at the time of death, sex, race, and cause of death as indicated by ICD-10 codes. CEHI used residential address to geocode each record and spatially link it with the corresponding 2010 census block group identifier. We dropped records for individuals not living in North Carolina at the time of death, records not matched to a census block group, and duplicate records . Because this study focused on cardiovascular mortality among older adults, we further restricted the sample to individuals age 65 or older at the time of death with a disease of the circulatory system listed as the primary cause of death (ICD-10 codes I00-I99) .  at the University of Notre Dame. The analysis was conducted according to a research protocol approved by the University of Notre Dame’s Institutional Review Board. We used individual mortality records from North Carolina from 2000 to 2017  provided data on location and aviation traffic for North Carolina airports from a variety of sources . We obtaThe FAA Traffic Flow Management System Count (TFMSC) and Air Traffic Activity Data System (ATADS) databases provide more detailed aviation traffic data but for fewer airports ,36,37. TATADS includes operations data for approximately 500 US airports with air traffic control towers. ATADS includes both IFR and VFR operations, making it a more comprehensive data source than TFMSC in terms of number of operations. However, it does not provide the engine type; instead, it categorizes operations by user class . . The EPA estimated that roughly 70% of general aviation and 20% of air taxi operations used piston-engine aircraft and, hence, leaded fuel . The ATAFor each airport with TFMSC data, we obtained the number of IFR departures and arrivals at each airport for each calendar year during 2000–2017 by aircraft engine type  and size . Piston engine flights were of primary interest in our study because they use leaded aviation fuel. Jet and turbine aviation traffic do not use leaded fuel but are important to control for because they generate other pollutants, such as particulate matter, volatile organic compounds, and noise, which are associated with adverse cardiovascular morbidity and mortality . Piston-Although the data were not as detailed, we were also interested in the number of general aviation VFR operations at each airport in each year. Because most general aviation activity uses piston-engine aircraft, and most other flight types do not , we usedWe linked each 2010 census block group in North Carolina to the closest TFMSC airport using geodesic distances calculated from each census block centroid to the nearest runway at the airport. A spatially explicit FAA data layer of the runway footprints was obtained from ESRI ArcGIS Online . We condWe focused our analysis on forty North Carolina airports that met the following three criteria: (1) data on piston-engine IFR flight operations from TFMSC were available; (2) data on general aviation operations from ATADS or 5010 reports were available; and (3) there was at least one census block group with a centroid located within 2 km of the airport runway(s). We focused on airports with populations within 2 km because past empirical research found effects on children’s BLL to be concentrated within a few kilometers of airports ,7. TwentIn 2010, out of 6155 census block groups in North Carolina, 1764 fell within 10 km of one of the 40 airports shown in We incorporated demographic and socioeconomic variables for each block group into the analysis using data from the 2000 and 2010 Decennial Censuses of Population and Housing and the American Community Survey (ACS) five-year estimates for each five-year period from 2006–2010 to 2015–2019 downloaded from the IPUMS National Historical GIS Information System .  model . For eacWe linked each census block group to non-TFMSC airports and heliports and roadways, which could also be sources of lead and other pollutants. Non-TFMSC airport and heliport locations were represented by FAA Airport Reference Points. Roadway data came from the US Census Bureau’s TIGER/Line files . We alsoWe included two additional county-level control variables that could affect cardiovascular mortality trends over time: the unemployment rate and exposure to heat waves, as measured by the number of days exceeding 90 degrees Fahrenheit ,49. We oSimilar to other studies of aircraft emissions e.g., ,21,28), ,28, 21,2Our outcome variable was the number of cardiovascular deaths among individuals age 65 and older in each block group and year. Our key exposure variables were proximity to the closest TFMSC airport and the numbers of piston-engine and general aviation flight operations at the closest TFMSC airport during the corresponding year.We used a Poisson model to estimate the relationship between mortality and exposure to aircraft operations, adjusting for several other explanatory variables see . The PoiWe first estimated a model to examine the association between cardiovascular mortality and proximity to the closest TFMSC airport. The model includes several control variables to adjust for other risk factors besides leaded aviation fuel emissions. These include the sociodemographic variables discussed above, industrial stationary source emissions, and, for 18 airports in our sample, a time-invariant measure of airport noise. While block group fixed effects would further control for time-invariant socioeconomic and geographic determinants of mortality, we did not include them in this model because they are perfectly collinear with the airport proximity variables, which are of primary interest. Because we did not use block group fixed effects, we interpreted the coefficients of this model as correlations rather than causal effects.The airport proximity model can be written as:icatm represents the number of cardiovascular deaths in the 65 and older population in block group i, in county c, located closest to TFMSC airport a, during year t. We modeled icatm as a function of several variables, including the offset term representing the natural log of the number of people age 65 and older in block group i in year t (pop65it). The coefficient on the offset term was constrained to equal one. iaD is an indicator variable denoting that the population-weighted centroid of block group i is within a given distance of airport a. Due to the uncertainty about the spatial extent of any adverse effects from aircraft operations on cardiovascular mortality, we estimated the model three separate times using different distances to reflect possible treatment groups: 0–1, 0–2, and 0–3 km. To further examine heterogeneity with respect to distance, we also estimated a single regression that includes three mutually exclusive distance indicators: 0–1, 1–2, and 2–3 km.  is a vector of mutually exclusive indicators denoting incremental distance bins).Here, ictX), including airport noise, proximity to major roads, unemployment, and time-varying block group socioeconomic characteristics. Year-specific intercepts for each year of the analysis (tY) were included to capture statewide trends over time. Separate intercepts denoting the closest TFMSC airport (aB) captured time-invariant location- and airport-specific factors affecting mortality rates, albeit at a relatively coarse geographic resolution. We also included a linear time trend that is specific to each airport, represented by We included a vector of block group and county control variables (iaD) and characteristics of that airport , large jet or turbine (iatLG), and small jet or turbine (iatSM) IFR aviation operations and the number of general aviation VFR operations (iatGA) at the closest airport a to block group i during year t. We interacted these aviation variables with iaD, the airport proximity indicator corresponding to block group i’s location. These interaction terms are our key explanatory variables representing possible exposure to leaded aviation fuel emissions near airports, given by ia * PEiatD and ia * GAiatD. Therefore, We included the numbers of piston-engine  and (2), respectively). We used census tracts instead of block groups as the unit for clustering in the annual flight operations model to allow for any unobserved spatial correlation in cardiovascular mortality that may occur within broader neighborhoods.We separately estimated these models for block groups near single-runway and multi-runway airports. We disaggregated by the number of runways because we anticipated that our measure of proximity to airport traffic is more precise for single-runway airports. For airports with more than one runway, there may have been greater dispersion of emissions across space, and we lacked data to apportion flight operations to specific runways at each airport, creating uncertainty about where the emissions occurred and hence which block groups were more exposed to air traffic emissions. This potential for classical measurement error in our measure of air traffic exposure at multi-runway airports could bias our estimates of the impact of aircraft operations on mortality towards the null.We also estimated specifications of the airport proximity and annual flight operations models that incorporated wind direction. For the airport proximity model, we interacted the percentages of days a block group was downwind and upwind of the closest TFMSC airport with the indicators for distance from the airport. For the annual flight operations model, we added terms capturing the three-way interactions between annual flight operations, distance from the airport, and percentages of each year the block group was downwind and upwind from the airports. In these models, we also included a dummy variable indicating block group-year observations for which wind direction data were unavailable (corresponding to 10 percent of observations).Our original models that do not include interaction terms with wind direction estimate average effects for all populations equidistant around airport runways. These estimates do not reflect spatial heterogeneity that could arise if wind dispersion of lead particles causes higher lead exposures from piston-engine air traffic for populations downwind and lower exposures for those upwind of airports. However, because runways often run parallel with the prevalent wind direction, models assuming directional homogeneity (as in Equations (1) and (2)) could be more appropriate for reflecting exposures to populations living along the sides of runways, where startup, idling, and taxiing emissions could also generate high concentrations of lead in the air.iaD of a TFMSC airport are comparable in terms of socioeconomic characteristics that could affect cardiovascular mortality to the “control” block groups located farther away (but still within 10 km), our primary estimates used coarsened exact matching (CEM) [To ensure that the “treated” block groups located within ng (CEM) . CEM is We matched our treated and control samples using seven coarsened block group sociodemographic variables and three non-coarsened variables. The coarsened variables include median income, population density, the share of the adult population that graduated from college, the share of the population that was Black, the share of population that was 65 and older, the share of housing that was renter-occupied, and the share of housing that was built before 1950. We divided median income into tertiles, and for all other coarsened variables we created three categories defined by equally spaced cut points. We matched on the 2010 values for all census variables. The three variables used for an exact match were county, year, and closest airport. In balancing observable sociodemographic characteristics across the treatment and control groups, this strategy may also increase similarity in unobservable traits that are correlated with the observable characteristics.We generated three sets of CEM weights corresponding to three possible cutoffs delineating the treatment and control groups already discussed: 1 km, 2 km, and 3 km from the closest TFMSC airport. The Our preferred approach combining panel data, block group-specific intercepts, and matching allows us to more credibly isolate the effect of piston-engine aviation on cardiovascular mortality based on year-to-year changes in air traffic. The airport proximity model (Equation (1)) is less able to isolate this effect because airport proximity could be correlated with socioeconomic or other local attributes affecting cardiovascular mortality. The flight operations model interacting distance from the airport with annual aviation operations (Equation (2)) is conceptually similar to a quasi-experimental difference-in-difference model, although the exposure variable representing number of flight operations varies continuously over time rather than changing discretely at one point in time.Our full sample included 31,495 census block group-year observations. . Using CEM to focus our analysis on a more homogenous matched sample of treated and control block groups greatly reduced the sample size. Using a treatment definition of 2 km, we kept 81% of treatment observations and 28% of control observations and were left with 9997 observations. Since most of the “pruned” observations were in the control group, we retained most observations in the treatment group closest to each TFMSC airport. Therefore, CEM helped us to identify the most appropriate counterfactual set of block groups. Using a treatment definition of 1 km yielded a much smaller matched sample of 1552 observations, while a treatment definition of 3 km yielded a larger matched sample of 14,245 observations.The matched treatment and control groups near multi-runway airports have sociodemographic and housing characteristics that are similar to each other, though incomes were somewhat higher in the control group. Air lead concentrations from stationary industrial sources were also higher in the control group. The differences between the single-runway and multi-runway samples are more pronounced than the differences between the treatment and control groups for each airport type. Income and education levels were much higher, and the share of Black and Hispanic residents was much lower, near single-runway airports. These divergent demographic characteristics further support our decision to analyze single-runway and multi-runway airports separately.We also found a significant increase in cardiovascular mortality of 0.03 percent per piston-engine IFR operation within 1 km of multi-runway airports but found no significant effect from changes in piston-engine IFR operations beyond this localized area. As already noted, at multi-runway airports, we have lower confidence that the distance between populations and airport runways is a good proxy for exposure to leaded fuel emissions because we do not know which runway was used for each operation.Turning to the other flight types, the results suggest that general aviation VFR flights were negatively associated with cardiovascular mortality within 0–1 km of multi-runway airports but had no statistically significant effect on cardiovascular mortality at any other distances. The negative association is counterintuitive, but as already noted, our VFR flight data lack accurate year-to-year variation at most airports given their exclusion from the TFMSC database. In addition, while most general aviation VFR flights are thought to be piston-engine, our data did not confirm engine type . Moreover, piston-engine IFR operations are more likely than VFR operations to be performed by twin engine aircraft, which have higher lead emissions per operation than single-engine aircraft.The effects from small and large jet or turbine flights on cardiovascular mortality are also not significantly different from zero in most specifications. The exception is a significant adverse effect of large jet and turbine operations within 0–1 km of single-runway airports and a marginally significant adverse effect of small jet and turbine operations on cardiovascular mortality within 0–3 km of single-runway airports. Large jet and turbine aircraft have the potential to cause adverse effects from both conventional pollutant emissions and noise near airports. In addition, if smaller jet and turbine operations emit very fine particulates that disburse with wind, then adverse health effects could occur further from airports. The magnitude of the coefficients on small and large jet/turbine operations at single-runway airports is similar to that of the piston-engine IFR coefficients using the 0–3 km treatment definitions. Overall, these results suggest that piston-engine IFR flights were relatively more harmful to cardiovascular health than similarly sized flights in areas located closest to single-runway airports but that these effects may converge or even reverse a few kilometers away from the airports.In contrast to The estimates of the effects of other flight types on cardiovascular mortality from The primary finding that piston-engine IFR operations had a statistically significant adverse association with cardiovascular mortality within 0–1 and 1–2 km from single-runway airports is robust to alternative specifications that use the full sample without CEM weights and to models that exclude other operation types p = 0.28)). The latter illustration is of interest because it may better isolate the effects associated with leaded fuel emissions. Small jet and turbine IFR flights do not use leaded fuel but may emit similar levels of other pollutants and noise that could contribute to cardiovascular mortality.We provide an illustrative example of the magnitude of the adverse effect of piston-engine aircraft on cardiovascular mortality by calculating the impact of a 10 percent reduction in operations near single-runway airports. Using the coefficients for the 0–2 km treatment effect from column 1 of p = 0.08). The wind interaction model suggests that the counterintuitive negative association seen within 1 km of single-runway airports in Next, we consider how wind direction modifies the relationship between exposure to piston-engine aircraft traffic and cardiovascular mortality. Near multi-runway airports, cardiovascular mortality rates were significantly higher downwind within 1 km of the closest runway. The other proximity-wind coefficients in the multi-runway model did not show a clear monotonic trend and were not statistically significant. Overall, these results suggest that cardiovascular mortality rates among individuals 65 and over were higher near and downwind (but not upwind) of both single- and multi-runway airports. However, they do not identify to what extent these effects were caused by aircraft operations or by residual confounding from other cardiovascular disease risk factors that could be correlated with living downwind of airports.Similar to p = 0.12 for test of joint significance). These results are consistent with our previous findings of no detectable adverse effects from year-to-year changes in piston-engine operations near these larger, multi-runway airports.Near multi-runway airports, cardiovascular mortality rates were not significantly higher closer to the runways in years with more piston-engine IFR operations closer. The downwind and upwind interaction terms also lack statistical significance both individually and jointly (Our analysis indicates that increases in annual IFR piston-engine air traffic are associated with significant increases in cardiovascular mortality among adults age 65 and older living near single-runway airports. However, our data have several limitations—most notably, the lack of data on aviation lead air emissions, which are the exposures of interest. Blood lead surveillance data for adults or monitored air lead concentration data would provide a more precise measure of lead exposure from piston-engine air traffic. Our reliance on airport proximity and aircraft operations as imprecise proxies for exposure to lead emissions could lead to bias in our estimates. This bias could be downward due to classical measurement error or upward due to the confounding of lead emissions with other air emissions and noise from piston-engine operations.Our measure of general aviation VFR flights is particularly coarse as an indicator of lead exposure. Our data source for VFR general aviation flights did not distinguish between piston- and non-piston-engine aircraft, though EPA has noted that most of these flights are piston-engine . VFR fliBecause leaded fuel usage can vary across parts of an airport, there is also uncertainty about the specific location of the lead emissions, leading to classical measurement error. This source of measurement error should be less pronounced for single-runway airports. Our use of population-weighted block group centroids instead of individual residential addresses to calculate both distance and downwind/upwind measurements exacerbates this source of measurement error, further biasing our results toward the null. However, our finding of more pronounced adverse effects near single-runway airports is consistent with other research finding higher soil lead levels near single-runway airports in Oklahoma .We incorporated wind direction to account for potential spatial heterogeneity in air lead exposure at different distances to runways. However, our approach was not a spatially or temporally refined atmospheric dispersion model that would reflect variation in factors such as meteorological conditions, topography, and particulate sizes. Coupled with our proximity and aircraft operations variables, our measures of the percent of time each population-weighted block group centroid was downwind or upwind of the nearest runway provide a relatively coarse proxy for air lead exposure.Our primary analysis focused on the effects of year-to-year fluctuations in piston-engine air traffic. A key uncertainty in the scientific literature is the timing and duration of lead exposure resulting in adverse cardiovascular effects . If cardOur study was also limited to airports large enough to report data on piston-engine IFR flights to FAA, as reflected in the TFMSC database. We cannot assume that estimates of the impact of aviation traffic at larger airports are generalizable to smaller airports, which are likely to have fewer based aircraft and flight operations. Some of these smaller airports could be located closer to residential neighborhoods than larger airports if local zoning does not require setbacks, so lead emissions from these airports could still raise public health concerns. We did not conduct an analysis of proximity to smaller airports as a proxy for exposure because airport location could be correlated with socioeconomic and other determinants of cardiovascular mortality, making it challenging to isolate the effect of piston-engine air traffic holding all other risk factors constant with this approach.As already noted, there is potential for omitted variable bias if neighborhoods near airports were systematically different from those farther away. We used several strategies to minimize this potential bias, particularly in the flight operations regressions. These strategies included spatially refined census block group intercepts, coarsened exact matching on several socioeconomic characteristics that were associated with cardiovascular mortality rates, and the inclusion of numerous time-variant control variables and linear airport-specific time trends. To minimize bias due to the potential confounding of aircraft lead emissions with aircraft noise and other pollutants that can cause cardiovascular damage, we adjusted for aviation noise in our airport proximity regressions and accounted for large and small jet- and turbine-engine operations in our flight operations models. Despite this multi-pronged approach, we cannot assert with 100% confidence that we eliminated all sources of bias.Given the potential for our results to be biased towards the null, it is notable that we estimated statistically significant increases in annual cardiovascular mortality from an increase in piston-engine IFR air traffic for block groups up to 2 or 3 km of single-runway airports. The magnitude of these effects is similar to findings from other studies examining associations between airport pollution and cardiovascular disease. For example, Schlenker and Walker found that a one standard deviation increase in aircraft carbon monoxide emissions caused a 9 percent increase in daily mean hospital admissions for heart problems near California airports . This rePiston-engine aviation is the largest remaining source of airborne lead emissions in the United States. Our study is the first to estimate the effect of piston-engine aircraft operations on cardiovascular mortality among adults age 65 and older. The findings are mixed but suggestive of adverse effects. We found higher cardiovascular mortality rates within a few kilometers downwind of airport runways, though these results were not always statistically significant. We did not consistently find that cardiovascular morality was significantly higher in years with more piston-engine IFR operations at multi-runway airports, nor do we find higher mortality in years with more general aviation VFR operations, possibly because our measure of leaded avgas exposure is less precise in these cases. Spatial precision is important in contexts like this one, where the disamenity is very localized. However, we found that adults age 65 and older living within a few kilometers and downwind of single-runway airports had significantly higher cardiovascular mortality rates in years with more piston-engine IFR operations compared to adults living farther away from these airports.To obtain more reliable and precise estimates of the effect of leaded aviation fuel emissions on cardiovascular outcomes, a direction for future research is to conduct similar analyses using a larger sample of airports with reliable flight operations data. Data on the variation in air lead concentrations and/or adult blood lead levels over time near airports would further expand opportunities to identify the health effects of changes in adult lead exposure. In addition, a more comprehensive dataset of individual-level health and location data for the entire population of adults age 65 and older living near airports—not just those who experience a fatality or other significant adverse effect—would allow for a more spatially refined analysis based on the distance from individuals’ residences to the closest airport runway. In the meantime, our study presents preliminary evidence that reducing emissions from leaded aviation fuel could have significant health benefits for adult populations who are often overlooked in discussions of lead exposure.


Superior vena cava syndrome (SVCS) is an entity that has become more frequent dueto the increasing use of indwelling central venous catheters. Surgicalmanagement is considered in patients with extensive venous thrombosis and whenendovascular therapy is not feasible. The use of superficial femoral vein is anexcellent technique for reconstruction of the brachiocephalic vein and superiorvena cava (SVC) in cases with benign and malignant etiologies. We describe twocases of SVCS that were managed surgically at our institution with replacementof the SVC and brachiocephalic veins with a superficial femoral vein grafttechnique. Malignancy is the leading cause ofSVCS in 60-80% of the cases,4; however, the incidence ofnonmalignant causes has been increasing secondary to the expanded use of indwellingcentral venous catheters and cardiac pacemaker wires,3,5. Up to 40% of all patients withcentral venous lines develop thrombosis and 1-14% develop SVCS.About 17,000 patients develop symptoms of venous congestion of the head and neck dueto occlusion of the superior vena cava (SVC) and brachiocephalic veins in the UnitedStates of America every year. Percutaneoustransluminal angioplasty and stenting are the most frequently used strategies forSVCS of malignant etiology with concomitant thrombolysis therapy in selectedcases.Patients can be managed with conservative measures, endovascular therapy, or opensurgical approach,3,5. There are several types ofconduits for SVC and brachiocephalic vein reconstruction, from autologous grafts —such as superficial femoral vein (SFV), spiral saphenous vein, and pericardialtubular conduits — to expanded polytetrafluoroethylene prosthetic grafts.Surgical reconstruction is usually considered in patients with extensive venousthrombosis not suitable for endovascular treatment, also in those with failedpercutaneous interventions and refractory symptoms. The SFV was one of the firstbypass conduits used for reconstruction of SVC.The first report of SVC bypass was published in 1951 by Klassen et al.We describe a technique of SVC and brachiocephalic veins reconstruction with an SFVgraft in two patients who developed SVCS and were managed at our institution. TheFundación Cardioinfantil ethics committee approved the study (MinutesNº25-2021). All the procedures in this study were in accordance with the 1975Helsinki Declaration, updated in 2013.A 35-year-old male patient with a history of chronic autoimmune renal failure onhemodialysis for four years required placement of several jugular indwellingcatheters and developed SVCS in the last two years. At an outside hospital, theyfailed doing endovascular therapy. The patient was transferred to ourinstitution looking for definitive treatment. Computed tomography (CT) andinvasive angiography imaging confirmed diagnosis . A new aThe patient underwent bilateral internal jugular vein to SVC bypass surgery withinterposition of a reversed SFV autograft harvested from the left lower limb.Through a medium sternotomy extending to the neck, the thrombosed SVC andbrachiocephalic veins were identified, the graft was placed with an end-to-sideproximal anastomosis to the SVC and an end-to-side distal anastomosis to theright and left internal jugular veins with an end-to-side neo-confluent, thiswas performed without using cardiopulmonary bypass . The patFollow-up was conducted with venous phase computed tomography angiography (CTA). The patA 17-year-old male patient consulted with us because of a one-year history offacial and right upper limb edema, which were confirmed on physical exam. Thepatient had had a resection of a mature teratoma two years before and receivedcomplementary chemotherapy and percutaneous embolization. He arrived at ourclinic with a CT scan showing SVC and brachiocephalic veins obstructionsecondary to thrombosis, that was also observed on transesophagealechocardiogram , for whiWe decided to perform a surgical treatment with a bilateral internal jugular veinto right atrium bypass procedure using a reversed SFV autograft harvested fromthe left lower limb without cardiopulmonary bypass . SurgicaTracheal extubation was successfully accomplished in the operating room. Thepatient did not require any vasoactive drugs at the intensive care unit, wastransferred to a general ward on postoperative day two, and was discharged homeafter four days of surgery. The patient was asymptomatic for a year;nevertheless, follow-up CT scan revealed a teratoma recurrence and he died oneyear later. made thelargest published review of 13 studies, including 87 patients who underwent opensurgical repair with better long-term patency rates compared to 136 patients whoreceived endovascular therapy.Although both open and endovascular treatments of SVCS have shown good results,Sfyroeras et al.,8. Doty et al.,10 described 16patients who underwent SVC bypass with spiral saphenous vein graft for SVCobstruction secondary to benign disease; they observed the long-term results andreported 14 out of 16 patients with 87.5% grafts remaining patent at a mean of 10.9years of follow-up and all patients, except for one, were free from SVCS. Thelongest follow-up lasted for 23 years and eight months.Surgical replacement of the SVC with autologous vein grafts has been shown to haveexcellent long-term results in terms of patency in contrast to syntheticgrafts reported their experience in 42 patients using SFV grafts,showing secondary patency rates of 100% at 30 days, 97.1% at one year, 89% at threeyears of follow-up , and survival rates over86% at three years of follow-up .SFV grafts are a versatile type of conduits that have been used for arterial andvenous reconstruction. Brahmanandam et al.. TheSFV has a theoretical antithrombogenic benefit over spiral grafts, because it lackslong suture lines, requires less incisions, and does not demand so much time forgraft construction,6.Among the advantages of using SFV grafts we can find: the SFV does not require to bemodified prior to use, it is similar in size to the internal jugular vein, it has anaverage large caliber and length, also it can be easily harvested with approximately30-cm graft available from the confluence with the profunda femoris to theabove-knee popliteal veinIn our cases, we were able to see a benign condition secondary to jugular indwellingcatheters thrombosis where the brachiocephalic veins and SVC reconstruction wasachieved uneventfully with complete resolution of the symptoms. Even though thefollow-up period is still short, the graft has shown a satisfactory behavior.Unfortunately, the second case had a relapse of a malignant teratoma almost twoyears after successful SVC reconstruction which precluded the possibility ofdetermining the long-term patency of the graft.Using an SFV graft to treat severe SVCS is an excellent choice given the goodlong-term patency rates and the fact that grafts can be easily harvested with verylow morbidity. In patients with benign disease, it is preferable to use anautologous vein graft, especially because these patients have a longer lifeexpectancy.


Cortical thickness value (n = 1066) of the right superior frontal gyrus (SFG) showed not only positive correlations with short-term perceived stress and neuroticism, but negative associations with cognition. The chain mediation model found that the right SFG and neuroticism play a small but significant chain mediating effect between stress and total cognition. The strength of the resting-state functional connectivity (n = 968) between the left orbitofrontal cortex versus the left superior medial frontal cortex was positively correlated with crystallized cognition and negatively associated with conscientiousness. These results extend previous findings by the impacts of short-term perceived stress on cognitive function is mediated by neuroticism and the right SFG was the underlying neural mechanism.Perceived stress impairs cognitive function across the adult lifespan, but the extent to which cognition decline is variable across individuals. Individual differences in the stress response are described as personality traits. Substantial individual differences in the magnitude of cognitive impairment that is induced by short-term perceived stress are poorly understood. The present study tested the hypothesis that the relationship between short-term perceived stress and different aspects of cognition is mediated by personality traits. The study included 1066 participants with behavior and neuroimaging data from the Human Connectome Project after excluding individuals with missing variables. In the result, the parallel multiple mediation model demonstrated that the influence of perceived stress on the total and crystalized cognition is mainly mediated by neuroticism (indirect effect = −0.04,  Perceived stress is a feeling about how much strain individuals perceive when environmental demands exceed their adaptive capacity . The prePerceived stress or challenge might enhance cognitive performance in some situations while limiting performance in other situations. Mild stress could help to enhance cognitive function, particularly in memory tasks or when the cognitive load is not excessive , 6. ExpoPersonality traits also influence the cognitive function across the adult lifespan and correlate to mild cognitive impairment in older adults , 25. PrePrior imaging studies have observed that stress induces remodeling of the prefrontal cortex (PFC) and affects both the structure and function of PFC , 35. ChrBased on previous studies, we hypothesized that the relationship between short-term perceived stress and different aspects of cognitive function  is mediated by personality traits  in young adults. The data that were analyzed in the present study were derived from the HCP database, which included behavioral, magnetic resonance imaging (MRI), and genetic data that were collected from 1206 young adults. We sought to form a framework to explain how different personality traits mediate the effect of short-term perceived stress on different aspects of cognition decline and further explore the underlying neuroimaging mechanism by analyzing MRI data to probe the validity of our explanations and posited mechanisms.The data in the present study were drawn from the HCP database (March 2017 public data release) from the Washington University-University of Minnesota (WU-Minn HCP) Consortium , 45. TheThe short-term perceived stress of the participants in the HCP was assessed by the perceived stress scale in the National Institutes of Health (NIH) toolbox , which mPersonality was measured by the 60-item version of the Costa and McRae Neuroticism/Extroversion/Openness Five-Factor Inventory (NEO-FFI) . The NEOCognition was measured by a series of tests in the NIH Toolbox cognitive battery . ComposiDiagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV], criteria for alcohol dependence), tobacco dependence diagnosis (DSM-IV criteria for tobacco dependence), marijuana dependence diagnosis (DSM-IV criteria for marijuana dependence), and positive tests for illicit drugs . The correlations among short-term perceived stress, personality traits, and cognitive function were calculated using partial correlation analyses after controlling the above covariates using SPSS 20 software. False discovery rate (FDR) was used to address the issue of multiple comparisons, and FDR-corrected p values  < 0.05 were considered statistically significant.All of the analyses used the following variables as covariates: age, gender, race (categorized as white or other), handedness (Edinburgh Handedness Questionnaire scores), years of education, total household income, body mass index (BMI), adult self-report (ASR) anxious/depressed raw score, alcohol dependence diagnosis  and T2-weighted (T2w) structural images were acquired on a 3T Siemens Skyra scanner  with a 32-channel head coil at a resolution of 0.7 mm isotropic . The structural (T1w and T2w MRI) data used in this study were from the HCP preprocessed pipeline and composed of FreeSurfer summary statistics data, including surface thickness, surface area, and subcortical segmentation volume , 56. Thez transformation to improve normality. Resting-state functional connectivity (FC) between brain areas, which reflects correlations of activity, has broad implications for the interpretation of the brain regions with altered connectivity in the process of cognition and behavior. The linear regression models were constructed between behavior data and the whole-brain functional connectivity (FC) network , which reflected correlations between brain regions with altered connectivity and function after controlling the basic covariates [p values for each component using 5000 permutation testing were used to address the issue of multiple corrections, and the component with pval_fdr < 0.05 was considered statistically significant. Since the parcellation of the Shen brain atlas is based on objectively functional connectivity analysis [The resting-state functional MRI (rs-fMRI) images were acquired on a 3T Siemens Skyra scanner with a 32-channel head coil at a resolution of 2 mm isotropic . The rs-fMRI data has been preprocessed by the HCP with its uniform method , 55, 56.variates . FDR-coranalysis , we usedr = −0.08, pval_fdr < 0.05) and fluid cognition . Short-term perceived stress negatively correlated with agreeableness and conscientiousness . The correlation between openness, extroversion, and short-term perceived stress was nonsignificant. Total cognition positively correlated with openness, and negatively correlated with conscientiousness and neuroticism (Table After deleting individuals with missing variables, a total of 1066 participants with behavior and brain structure data from HCP were used for the analysis. The analysis flowchart is shown in Supplementary Fig. ss Table . Only nesm Table .Table 1DThe simple mediation analysis found that the relationship between short-term perceived stress and total cognition was mediated by neuroticism, conscientiousness, and openness respectively (Supplementary Table For the whole-brain analysis after FDR correction, the linear regression models revealed that the cortical thickness of 10 brain regions was significantly associated with short-term perceived stress, including bilateral SFG, bilateral rostral middle frontal gyrus, bilateral caudal middle frontal gyrus, right pars opercularis gyrus, left pars orbitalis gyrus, left pars triangularis gyrus, and left precentral gyrus. Neuroticism was significantly associated with the cortical thickness of right SFG, whereas no significant brain region was associated with the other personality traits Table . Total cTo further analyze the role of right SFG, we constructed the chain mediation model of the right SFG and neuroticism between short-term perceived stress and total/crystallized cognition Fig. . For totAfter excluding 98 participants without four fMRI scans, the rs-fMRI analysis included 968 participants. The linear regression models showed that all three measures had significant network FC after FDR correction. Further comparisons found overlapping FC in Shen brain atlas between conscientiousness and crystallized cognition, whereas no overlapping FC was found for perceived stress and other personality traits Fig. . ConscieIn the present study, we examined the mediation effect of different personality traits on the relationship between short-term perceived stress and total/crystallized cognition and explored the potential mechanism based on neuroimaging data. The relationship between stress and cognition was mediated by neuroticism, conscientiousness, and agreeableness. The mediation effect of neuroticism and agreeableness modulated the adverse effect of short-term perceived stress on cognition, whereas conscientiousness mitigated this adverse effect. The total effect, which was a combination of the direct effect of stress and indirect effect of personality, indicated that stress was negatively associated with total/crystallized cognition. Further neuroimaging analysis showed that right SFG cortical thickness was not only positively associated with stress and neuroticism, but also was negatively associated with total and crystallized cognition. The chain mediation model found that the right SFG and neuroticism play a small chain mediating effect between stress and total cognition. Moreover, people with high conscientiousness had a worse cognitive function and exhibited the hypoactivation of FC between the left lateral OFC and left superior medial frontal cortex. Our study indicates that people with high neuroticism have a higher vulnerability to cognitive decline induced by stress, while people with low neuroticism have a lower vulnerability to cognitive decline induced by stress. These results broaden the understanding of the relationship between short-term perceived stress, cognition, and neuroticism, and indicate that the structural and functional changes of SFG may be underlying neural mechanisms.Short-term perceived stress was negatively associated with total/crystallized cognitive function, and the relationship was mainly mediated by neuroticism and conscientiousness, and partially mediated by agreeableness. Acute stress exposure and chronic perceived stress across the life span increase the neuroticism level , 59. IndThe modulatory effects of neuroticism and conscientiousness on this relationship were supported by the neuroimaging data. Firstly, the neuroimaging analysis found that right SFG cortical thickness was positively associated with perceived stress and neuroticism, and negatively associated with total/crystallized cognitive function. In addition, the chain mediation model further demonstrated that the cortical thickness of the right SFG and neuroticism play a small but significant chain mediating effect between perceived stress and total/crystallized cognition. The SFG, comprising one-third of the prefrontal cortex, contributes to higher cognitive functions and particularly to working memory and executive cognition . The PFCThe present study has several limitations. Firstly, the perceived stress in the study was measured by short-term perceived stress scales which assesses the degree to which situations are appraised as stressful in the last month and does not reflect the long-term stress level. Secondly, our study was based on whole-brain analysis without pre-defined regions of interest, and the further comparisons of results did not find overlapping FC in the AAL atlas. Therefore, the FC results are scattered and in-depth data analysis using another parcellation atlas is required to confirm the robustness of the current findings. Thirdly, the HCP data were cross-sectional without longitudinal follow-up, so it is difficult to prove a causal relationship between short-term perceived stress and cognitive function. Future studies should explore the influence of longitudinal changes in chronic stress and acute stress on cognitive function and the involvement of specific brain structure and neurocircuitry.The present study tested the hypothesis that short-term perceived stress is negatively associated with total/crystallized cognition, mediated by neuroticism, conscientiousness, and agreeableness. Our findings might be useful for understanding the neuroimaging mechanisms that underlie stress-related cognition decline and preventing and controlling the adverse effects of perceived stress among individuals with susceptible personality traits.Supplementary Materials


Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal lymphoma with an indolent natural course. The thyroid gland is an uncommon site of involvement. We aimed to investigate serial ultrasound features and the disease progression during the clinical course of thyroid MALT lymphoma.We searched our hospital’s pathology database  between January 2000 and July 2022. The medical records and serial ultrasounds of 11 patients with 12 thyroid MALT lymphoma foci were analyzed retrospectively.An enlarging neck mass, dyspnea, B symptoms, and neck lymphadenopathy were seen at diagnosis in 9 , 3 , 2 , and 9  cases, respectively. Eleven cases were concomitant Hashimoto thyroiditis. Common ultrasound features included bilateral or unilateral asymmetric goiter or large, solid, and very hypoechoic nodules  interspersed with linear, reticular hyperechoic, and enhanced posterior echoes , and neck lymph node involvement . The Thyroid Imaging and Reporting Data System (TIRADS) categories showed higher diagnostic accuracy  than real-time ultrasound  in evaluating thyroid lesions for recommendation of fine-needle aspiration (FNA). Serial ultrasound showed self-limiting changes in three cases, relapse in three cases after subtotal thyroidectomy and chemotherapy, large cell transformation (LCT) in one case after left lobectomy, partial remission in one case, and complete remission after chemo/radiation in four cases; progression to enlarged thyroid nodules occurred in three cases without treatment, with no obvious change observed after diagnosis. Three patients died during follow-up.On sonograms, solid large thyroid nodules or goiter with very hypoechoic and enhanced posterior echoes in the setting of Hashimoto thyroiditis should raise suspicion for MALT lymphoma. TIRADS categories can improve the ultrasound diagnostic efficacy for malignancy. Serial ultrasound examinations demonstrated self-limiting and indolent natures of thyroid MALT lymphoma. As the most common subtype of indolent lymphoma in China , mucosa-The 2017 American College of Radiology-TIRADS (ACR-TIRADS) showed good performance in the diagnosis of thyroid nodules (TNs) . In 2020The pathology database from January 2000 to July 2022 was reviewed, and 5,418 patients with thyroid malignancy and 37 patients with thyroid lymphoma were identified using the terms “thyroid”, “lymphoma”, “MALT”, “malignancy”, “carcinoma”, and “Hashimoto thyroiditis”. Eleven patients (three men and eight women) with MALT lymphoma were enrolled in this study. The median age was 63 years (range 58 to 80 years) at diagnosis. The inclusion criteria were as follows: ① pathologically proven thyroid MALT lymphoma by surgery or core-needle biopsy (CNB); ② thyroid ultrasound examinations were performed within 1–3 months at pathological diagnosis. Patient information was obtained from medical records and present condition was obtained by telephone follow-up.Thyroid sonography scanning with neck hyperextension in a supine position was performed, and static images were stored in a picture archiving and communication system (PACS). The median follow-up for patients was 9 years (range 2 to 16 years). The ultrasound patterns of thyroid lymphoma were classified into three types: nodular, diffuse, and mixed types –12. The The ultrasound features of TNs were assigned points and categorized based on the 2017 ACR-TIRADS and 2020 C-TIRADS , 9. The Continuous data of normal distribution  were described as mean ± standard deviation, and categorized data  were described as percentages. SPSS 24.0 software  was used for statistical analysis.All 11 patients had a 6-month to 10-year history of goiter, TNs, thyroid diffuse diseases, increased thyroid antibody and Hashimoto thyroiditis (over 10-year history in two cases) before diagnosis. Three patients had previous overt hypothyroidism and received levothyroxine. Eleven cases were pathologically diagnosed with concomitant Hashimoto thyroiditis. The most common symptom was a gradually or rapidly (within 1–6 months) growing neck mass or goiter in nine cases  and was followed by dyspnea  and accompanied B symptoms . Eleven patients presented with stage IE , stage IIE , stage IIIE , and IVE . Two cases  involved multiple extranodal sites constituting the stomach and intestine. Generalized nodal involvement was rare and only seen in one case . One patient had previously undergone intestinal excision and was diagnosed with MALT lymphoma 7 years before, and one case had been proved to be marginal zone lymphoma (MZL) of the lymph node by CNB 6 years before. One patient simultaneously involved thyroid and gastric, which was diagnosed pathologically by CNB and gastroscopy.Thyroid MALT lymphoma was classified into three patterns on sonograms Table 1.Based on the ultrasound features, the 2017 ACR-TIRADS and 2020 C-TIRADS showed similar diagnostic performance for thyroid MALT lymphoma. The excellent diagnostic efficacy of the two guidelines was higher than that of real-time ultrasound. The one exception was a case in which left thyroid with MALT lymphoma was misdiagnosed as mildly suspicious and benign disease on the basis of the ACR-TIRADS and C-TIRADS and did not meet the criteria for FNA. All details mentioned above are summarized in Serial ultrasound showed the natural disease course of thyroid MALT lymphoma and its response to the treatment. The indolent, self-limiting natures of thyroid MALT lymphoma were found and are illustrated in Thyroid MALT lymphoma is extremely rare, accounting for 0.2% 11/5,418) of thyroid malignancies and 29.7% 11/37) of thyroid lymphomas, within the range of 6–46.8% reported in some studies ,418 of t. Among 17 of thyrThyroid MALT lymphoma commonly presents as a rapidly or gradually enlarged neck mass and goiter leading to local compressive symptoms. This neck mass rapidly grows in a short time, which is rarely observed in Hashimoto thyroiditis . DyspneaMost thyroid MALT lymphoma presented as very hypoechoic solid enlarged nodules and/or goiter of tumor cell infiltration with enhanced posterior echoes on thyroid sonogram. Thyroid MALT lymphoma is composed of small B cells, including marginal zone cells with a prominent population of small and intermediate-sized lymphoid cells, accompanied by lymphoepithelial lesions and/or plasmacytic differentiation in some cases. The consistency of the tumor cells without any acoustic impedance results in enhanced posterior echoes. The rarest heterogeneous appearance of thyroid MALT lymphoma closely resembled Hashimoto thyroiditis, with multiple hypo/isoechoic micronodules (≤ 10 mm) interspersed within a normal sized left lobe gland. The pathological image and the sonogram showed the same size of the foci tumor cell infiltration. This is the first study to characterize the diffuse micronodular appearance of thyroid MALT lymphoma in the background of Hashimoto thyroiditis with normal-size gland. Diffuse micronodular disease with MALT lymphoma cannot be identified except with surgical pathology. Furthermore, from the dynamic perspective, the tumor developing course is the process of small single nodule or multiple tumor foci grow up to be nodular type, then progress to become mixed type and finally infiltrate throughout the thyroid to develop into diffuse type based on these patients’ serial ultrasound findings.Serial ultrasound showed variable internal echoes of thyroid MALT lymphomas. The internal echoes were very low hypoechoic , PEF of undetermined significance, and short linear, parallel linear, reticular/alveolate hyperechoic, sequentially appeared, and increased as the tumor grew up. Due to the heterogeneous appearance of thyroid MALT lymphomas on sonograms, differentiation of these lymphomas from benign diseases such as Hashimoto thyroiditis, goiter, hemorrhage in adenoma, and even cysts is difficult for radiologists with insufficient awareness of thyroid MALT lymphoma. In some cases with the nodular type, pseudocystic appearance or concomitant PEF of undetermined significance were often misdiagnosed as cyst or hemorrhage. Increased vascularity detected by color Doppler flow imaging (CDFI) and pulsed wave (PW) can be helpful to identify the pseudocystic nodule as solid. Approximately 90% of MALT lymphoma cases demonstrated increased disordered vascularity.In our study, only two cases of suspected lymphoma were reported by two radiologists with more than 10 years of experience. Therefore, there was a marked discrepancy in the clinical real-time ultrasound reports. Application of the 2017 ACR-TIRADS or 2020 C-TIRADS categories is very useful to address ultrasound diagnostic dilemmas and eliminate interobserver differences in terms of recommendations for FNA/CNB. Because CNB can yield a higher proportion of diagnostic results than conventional FNA , our patMALT lymphomas have an indolent natural course and are slow to disseminate. Because of their insidious onset, precise diagnosis of thyroid MALT lymphomas is usually obtained after a long time (1–10 years) from the initial visit. In this study, serial sonograms showed the complicated natural course of thyroid MALT lymphoma, that is, thyroid MALT lymphoma behaved alternating or sequential self-limiting, progression or being unchanged on serial ultrasound for many years . This seWith regards to treatment strategy, MALT lymphomas are sensitive and have a better response to local thyroid radiotherapy, which is followed by prolonged disease-free intervals. Early stage MALT lymphomas may be treated with radiotherapy alone without disease recurrence. The follow-up ultrasound showed thyroid reduced to normal size without the nodule in two cases after radiotherapy. Because radiotherapy may result in severe adverse events, observation or rituximab alone is also used. Stages III and IV refer to the treatment of rituximab combined with chemotherapy or observation . The mosThe role of surgical intervention remains controversial, and such intervention is typically incidental in the management of indolent MALT lymphomas for other indications, such as palliation in the setting of critical airway obstruction or stenosis, which can be replaced by corticosteroids and chemo/radiotherapy and temporary use of tracheal stent . Among tIn this study, the goiter reduced to a normal size and returned to hypo/isoechoic parenchyma after chemotherapy in three cases, complete remission was 100%. Two cases went through a relative long period of remission (8 and 9 years); one case died and another relapsed. The third case with systemic dissemination had a 6-year history of goiter, died of brain involvement and hemorrhage after 2.5 years. Combined chemotherapy for advanced-stage disease can achieve complete remission in 90–100% of patients. However, relapses are unfortunately common within 3–6 years (10–35%), which can occur after many years and may involve other extranodal sites. The 59-year-old woman with a 7-year history of MZL, concomitant lymphocytic leukemia and bone marrow involvement, survived for 9 years after chemotherapy and then died of lung infection. In summary, mortality  was unfavorable; survival to date was 8.5 years (2–16 years) in our study.In addition, three cases without treatment experienced a period of time  with no significant change of tumor, survived for many years  with disease-specific to date. We found thyroid MALT lymphomas disappeared, appeared, increased, shrunk, and even reoccurred on serial sonograms in two cases without treatment. Relapsed masses decreased in size in one case at 8 years after subtotal thyroidectomy during a long period of follow-up ultrasound. It is first time that the self-limiting changes of thyroid MALT lymphoma was demonstrated in the form of ultrasonic images, which has not been reported in the literatures we read. Thyroid MALT lymphomas in the above three cases  with self-limiting change showed paradoxical and complicated growing features. Although self-limiting growth seemed to show an excellent prognosis, it is difficult for MALT lymphoma to identify its growth arrest because it could restart proliferating and rapidly enlarging up to spread into diffuse goiter in the case of occurrence of self-limiting. The evolution is a bit different from those juvenile thyroid cancer and PTM . It is yThyroid MALT lymphoma follows a relatively benign course and historically demonstrates a better response to treatment. The 5-year disease-free survival rates approach 96–100%, higher than 71–75% for DLBCL and the other histological subtypes , 32. PooThere are some shortcomings in the present study. Surgical excision in three cases had superior diagnostic accuracy in comparison with CNB in eight cases. Biopsied tissue samples do not represent pathological features of entire tumor involvement with insufficient evidence, affecting the analysis of ultrasound characteristics. The other major limitation was the small sample size due to the morbidity and longer clinical course of thyroid MALT lymphoma, which failed to reach statistical significance. Further studies with large cohorts of patients and comprehensive analysis are needed to address this issue.Thyroid MALT lymphoma demonstrates an indolent natural course and a self-limiting trend. Most patients have an excellent prognosis. Thyroid ultrasound is the most sensitive method to detect thyroid MALT lymphoma. Enlarged very hypoechoic solid TNs or goiter with enhanced posterior echoes in the setting of Hashimoto thyroiditis on sonogram should raise suspicion for thyroid MALT lymphoma. Both the ACR-TIRADS and C-TIRADS categories can significantly improve ultrasound diagnostic efficacy to recommend FNA/CNB and decrease interobserver diagnostic discrepancy in clinical management. Serial ultrasound is helpful for better understanding of the indolent clinical course, self-limiting, relatively benign or aggressive behavior such as LCT, and better response to treatment management in thyroid MALT lymphoma. The TN risk stratification is also applicable to thyroid diffuse diseases. Active surveillance by the follow-up ultrasound TIRADS category can substantially screen significant malignancies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.XZ contributed to the conception and design of this study. Material preparation and data collection were performed by XZ, BW, LN, HZ, YG, and JO. Analysis was performed by XZ and BW. The first draft of the manuscript was written by XZ and BW. All authors commented on previous versions of the manuscript and read and approved the final manuscript.


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.