A journal club program was initiated in a clinically focused, geographically distributed medical physics therapy residency program. This program currently supports two residents at different clinical sites, who regularly present at the new journal club. For one of the sessions, residents were assigned to present on topics related to the broad themes of equity, diversity, and inclusion (EDI) in the context of medical physics, radiation oncology, or medical oncology. As in other journal club sessions, residents were responsible for choosing their respective articles within required criteria and with approval from the program director. The session was executed in late 2022, with both residents leading and facilitating discussion for the residents, the residency program director, and all residency faculty members. This education case report will include the learning objectives for the journal club session, a description of the content covered in the session, discussion regarding the session's alignment with the original learning objectives, and ideas for program directors intending to include evidence‐based EDI topics in journal clubs. The Commission on Accreditation of Medical Physics Education Programs (CAMPEP) Board is currently drafting standards addressing EDI that will apply to all CAMPEP‐accredited educational programs, including graduate, doctorate of medical physics, certificate, and residency programs , and the update to AAPM's TG‐249 regarding guidelines for clinical medical physics residency programs, currently under review, contains a section on EDI . Based on the critical need to increase equitable opportunities and workforce diversity and inclusion within the medical physics profession,1.1Northwest Medical Physics Center (NMPC) is a non‐profit medical physics service group providing medical physics consulting services to a variety of clinics throughout a geographically distributed region. They have sustained a CAMPEP‐accredited residency program in therapeutic medical physics since 2009, and currently support two medical physics residents who are stationed at two different clinical sites. The program hosts a quarterly, resident‐led journal club, modeled after best practices described by Cetnar.During the videoconference journal club meeting, the first presenting resident gives a prepared presentation, approximately 20 min long, that includes an introduction to the article(s), a discussion of why the selection was made, a review of key components, a critical analysis, and suggestions on how this work may be applicable to their practice. Following the formal presentation, the non‐presenting resident discusses how this work may or may not be applied to their own clinical site or to procedures they have seen in the past. After both residents have discussed the article(s), the presenting resident then leads and facilitates a discussion with all journal club members, discussing clinical and/or professional application of evidence‐based scholarship. This facilitated discussion lasts approximately 20 min. Faculty members are encouraged to contribute, but they are instructed not to dominate the discussion. All contributors are required to engage in respectful discourse. After the first resident has presented and facilitated a discussion for their topic, the second resident presents and facilitates the second topic. Feedback from all journal club members is collected following each journal club session, with possible adjustments made to following sessions based on this feedback.Residents will improve in professional scientific presentation skills and critical thinking/analysis of scientific, peer‐reviewed literature.Journal club members will better understand challenges faced by people of different identities, including those related to race, ethnicity, culture, gender, age, sexual orientation, ability, religion, economic status, language, national origin, and other backgrounds within the context of medical oncology, radiation oncology, and medical physics.The equity, diversity, and inclusion (EDI) journal club session will promote discussion about applying EDI topics in professional settings among club members.The following learning objectives were proposed for a journal club session focused on topics of equity, diversity, and inclusion at a medical physics residency program.1.2A theoretical framework is the lens through which scholarly work is approached, including the underlying concepts and theories that inform scholarly work.1.3Journal clubs are a conventional element of medical education, and these journal clubs frequently consist of evaluating and critiquing scientific articles revolving around evidence‐based medicine.1.4“Diversity based on race, ethnicity, and sex, of the US radiation oncology physician workforce,” by Chapman, Hwang, and Deville“Ethical violations and discriminatory behavior in the MedPhys Match,” by Hendrickson et al.“The state of gender diversity in medical physics,” by Covington, Moran, and Paradis“I can't breathe: The continued disproportionate exclusion of black physicians in the United States radiation oncology workforce,” by Deville et al.“Implications of medical board certification practices on family planning and professional trajectory for early career female radiation oncologists,” by Dover et al.“A qualitative investigation of resilience and well‐being among medical physics residents,” by Paradis et al.“Diversity and professional advancement in medical physics,” by Rankin et al.“2021 AAPM Equity, Diversity, and Inclusion Climate Survey Executive Summary,” by Hendrickson et al.For the EDI journal club session, residents were required to focus on studies related to EDI in the context of medical physics, radiation oncology, or medical oncology. The journal club leader selected eight peer‐reviewed articles that they believed could inspire thoughtful EDI discussion as example options. Residents were invited to pick from the list or make their own choices, with the request that any choices outside the list be discussed with the program director prior to finalizing the article choice. Each resident was required to present two articles. Residents were instructed to facilitate discussion regarding practical applications from each paper in relation to themes of EDI: what NMPC as a residency and the journal club members as medical physics colleagues can learn and improve on based on this work. The pre‐selected paper collection is included below:The EDI‐themed journal club was presented in late 2022. The first presenting resident led discussion on one article included in the list above, Hendrickson et al.2At the journal club session, the residents led a nuanced discussion about major EDI issues, including biased and discriminatory environments faced by some trainees, culturally competent care offered to patients, and disparate access to care for some patient populations. For the discussion regarding the article focused on ethical violations and discriminatory behavior in the MedPhys Match, the resident described their own personal experience with some of the illegal and unethical questions raised during their own match interview process. They asked the group to think about how questions regarding marital status or children may affect candidates in varying personal situations, such as candidates planning to marry their partner, candidates going through a divorce, or candidates experiencing pregnancy. For the discussion regarding the article evaluating disparities in access to radiation therapy among American Indian/Alaska natives and Hispanic patients in Washington State, the resident discussed resources and funding programs at their clinical site of practice to make care more accessible to patients with different levels of resources. Some of the examples discussed were parking available for RV trailers near the radiotherapy center, and social workers being actively involved in patient care, including attending and contributing to radiation therapy daily huddle mini‐conferences. A major discussion question the resident posed based on this article was regarding what medical physicists can do to better support accessibility efforts in their own communities. For the discussion regarding the article focused on diversity and professional advancement in medical physics, the resident posed questions to the journal club regarding how childcare needs and inequitable leadership promotion practices negatively impact some groups of physicists compared to others. The resident reviewed the lack of discussion within the paper regarding experiences of marginalized groups, but also noted that the paper included some suggestions on combating a lack of diversity that may be valuable. Among other topics, the resident asked the journal club members to consider ways to improve mentorship and networking opportunities for medical physicists and medical physics residents, as well as provide social, financial, and institutional support. For the discussion regarding the final article examining resilience among medical physics residents, the resident posed questions about the role of professional societies in addressing residency‐related change, including focusing on widespread burnout, strategies to cope with residency‐related stress, and the demanding nature of the match process, especially for candidates who may face additional barriers or discrimination.These topics are of importance to the AAPM, which adopted diversity and inclusion as components of their focus areas in 2018, with the strategic goal of championing equity, diversity, and inclusion in the field of medical physics.Educators interested in leading sessions dedicated to EDI topics in medical physics journal clubs, including those involving residents, are encouraged to review available resources, including emerging scholarship. Note that journal club leaders should review the body of literature beyond the list included earlier, as this area of research is currently active, and the available literature is continually expanding. For example, since the list included in the previous section was compiled, there have been thought‐provoking, evidence‐based articles, reviews, and book chapters published on ethics and artificial intelligence in radiation oncology,It is noted that the broad range of publications that could be used to explore EDI topics cover an extensive scope of problems, including the needs to improve workforce diversity, to reduce health care disparities and increase access to quality health care across the patient population, and to foster a culture of belonging within the profession. As noted by Ponce et al.,2.1The AAPM currently offers resources for residency educators hoping to host a journal club. The AAPM Work Group on Multi‐Institutional Journal Clubs for Residency Programs (WGJCRP) maintains group guidelines available by request for residency programs that intend to contribute to a distributed journal club . Interest in multi‐institutional journal clubs has been high among CAMPEP‐accredited medical physics residency programs, and the WGJCRP has facilitated the meeting of multiple national medical physics journal clubs since its formation in 2021. As of 2022, 40% of therapy and 50% of imaging and nuclear medicine accredited programs were participating in this voluntary multi‐institutional journal club program through WGJCRP.3A medical physics residency journal club session was held focusing on EDI topics in the context of medical physics, radiation oncology, and medical oncology. Four recent, peer‐reviewed journal articles were presented, with discussion led by residents. Residents and faculty members agreed that the broad objectives of the journal club were met in this session, and resident and faculty members considered the session useful as a platform to discuss EDI. Educators who are interested in incorporating EDI topics into journal clubs are encouraged to review some of the resources discussed in this case report, and acknowledge that all major concepts in equity, diversity, and inclusion cannot be adequately covered in a single journal club meeting. Exploring topics in EDI within the context of a residency journal club offers a complementary perspective on the discipline of medical physics to the usually technical and scientific topics explored in journal club sessions. Highlighting these issues through a journal club helps residents and faculty increase awareness of EDI issues.The first author designed and initiated the residency journal club, acted as journal club leader and organizer, researched the theoretical framework for the project, conceived the EDI journal club session, requested and received Steering Committee approval for the session, compiled the literature for the EDI session, coordinated faculty and resident attendance for the session, and wrote the manuscript. The second and third authors had equal contributions to the manuscript. Each researched and reviewed available literature, presented two EDI‐focused articles, and led discussion among the resident and faculty group. They reviewed and revised the manuscript.There are no relevant conflicts of interest to disclose.


In this paper, an electrostatic compliant mechanical amplifier intended for force-compensated displacement amplification in MEMS sensor applications is described. Usually, mechanical transformers that enhance a small input displacement into a large output displacement generate large forces at the input of the transformer. The microsystem proposed here allows for the reduction and compensation of the input stiffness of the amplifier and any mechanical components connected to it while providing a constant amplification ratio at the same time. The amplifying mechanism features bidirectional electrostatic anti-springs enabling the control of the stiffness by applying a constant DC voltage. The electrode design of the anti-springs and its influence on the force-displacement characteristic, the side instability and the maximal displacement are studied through analytical approaches and supported by FEA and by experiments. Based on the derived models, a compliant electromechanical amplifier is developed, featuring an amplification ratio of 50. For this amplifier the initial input stiffness of 422 N/m could be reduced to 6.8 N/m by applying a voltage of 100 V. As an additional application, we show how the amplifier can be used as a mechanical force sensor with tuneable sensitivity, where the forces at the input are transformed into large output displacements. Through experiments, we show how the sensitivity can be adjusted and increased by a factor of 25 by applying a voltage at the anti-springs. Mechanical amplifiers are also known from electrostatic8 or piezoelectric10 actuators to convert forces into large displacements.Compliant mechanical displacement amplifiers have been investigated for various applications and can be found in MEMS sensor systems for displacement or force amplification, such as in accelerometers or gyroscopes11, we presented the design and modeling of a passive lever-based compliant mechanical amplifier (mechAMP) with an amplification ratio of up to 200. An advantage of compliant amplifiers is that these mechanisms based on flexure hinges do not suffer from wear or backlash. However, compliant hinges generate force reactions in response to imposed displacements, which are also amplified within the mechanism. Additionally, the stiffness of additional springs connected to the output of an amplifying mechanism is increased, resulting in a very large stiffness at the input. Therefore, the resulting stiffness at the amplifier’s entrance strongly depends on the amplification ratio. When aiming for high amplification ratios, the mechanism usually requires extremely high forces at the entrance of the system that are often not compatible with the weak signal to be amplified.In previous worksIn this paper, we present a force-compensated mechanical amplifier featuring bidirectional electrostatic anti-springs, which allows the amplification of small displacements without feeding back high reaction forces. Furthermore, the proposed amplifier can be used as a mechanical impedance transformer, allowing the input stiffness of the amplifier to be individually set at a given amplification ratio.16. Basically, two methods of electrostatic stiffness adjustment for comb-drive actuators have been investigated thus far. One type focuses on varying the overlapping surface area of parallel plate electrodes in a comb drive by designing finger electrodes of different lengths, as presented in18. The number of finger electrodes contributing to the force generation varies with the displacement of the actuator. This allows discrete position-dependent force generation. Additionally, a variation of the surface area in the vertical direction that occurs by increasing the thickness of the finger electrodes using greyscale lithography has been introduced19.Electrostatic stiffness adjustment, as applied here for the mechAMP, is well known for other MEMS applications, especially for MEMS resonators20 first presented various electrode shapes that tailor the polynomial electrostatic force-displacement characteristics. An extended study for multiple electrode shapes was presented by Jensen et al.21. A detailed review of the methods for mechanical and electrostatic stiffness adjustment is also provided22. However, most of the known concepts are suitable for displacements in only one direction and often feature an offset in the force-displacement characteristic.Another possibility for electrostatic stiffness adjustment consists of the variation of the gap between the finger electrodes to achieve a displacement-dependent electrostatic force. Ye et al.For the realization of the force compensation of the mechAMP in this work, we pursue the concept of varying electrode gaps for a bidirectional and offset-compensated electrostatic anti-spring.In the section “System and Design”, the design of the electrostatic anti-spring is studied considering its limitations as well as the integration within the mechAMP. The fabrication process and the experimental model verification are presented in the section “Fabrication and Characterization”, while the section “Conclusion” is a summary of the main results.As shown in Fig. Based on the serial arrangement of the levers, a small displacement at the system entrance is amplified within two stages. A first amplification is obtained by the first lever and then again by the second lever. A higher cascading with additional levers is possible in principle. In a simplified approximation, the total amplification ratio Due to the cascaded arrangement, high amplification ratios can be achieved on a very small footprint. However, the ratio of the input stiffness High amplification ratios consequently result in high stiffness transformations from one side of the amplifier to the other side. To compensate for the high mechanical input stiffness, electrostatic anti-springs with a negative spring rate are designed and implemented at the output of the amplifier. Integrating the electrostatic anti-springs at the mechAMP’s input instead of the output would compensate the input stiffness as well; however, by implementing the anti-spring at the output, the stiffness conversion of (2) can be used to reduce the number of required anti-springs.x-direction. The superposition of both electrostatic forces results in:As shown in Fig. Here, The function 2] and the shifting parameter Supposing a position of the coordinate system, as shown in Fig. x, the negative spring constant of the electrostatic spring yields:After inserting (4) and (5) into (3) and dividing by the displacement As seen from (6), the spring rate mainly depends on the applied voltage COMSOL Multiphysics. The results of the analytic model and of the FEA are compared in Fig. a. Although Fig. To verify the model provided by (3) and (6), a finite element analysis (FEA) of different counter-spring designs was carried out in x-position, neglected stray fields limit the validity of the analytic model. To reduce such parasitic effects, the shifting parameter At small displacements around the initial y-direction in reference to its ideal position (5) is analysed. Here, the curved electrode is shifted to determine the impact of small y-displacements due to fabrication tolerances.Within the FEA, the impact of a small offset displacement Figure x-direction as a function of the electrode offset position a.The sensitivity of the constancy of the spring rate to the offset-displacement is analysed in Fig. a should be selected for the electrode design when aiming for high immunity to fabrication tolerances.Therefore, large values for Configuration A. Here, the combination of curved electrodes and parallel plate actuators is set up in a mirrored arrangement. To limit the influence of the parallel plate actuators to one direction of displacement, a gap is introduced at the end of each actuator. For Configuration A, we assume that the electrostatic force The proposed configuration in Fig. Configuration B, where only a mirrored arrangement of curved electrodes is used, and the parallel plate actuators are omitted. Due to the symmetric setup, the force offset within the force-displacement characteristic of the curved actuator is compensated by a counter force generated by the stray fields of the opposed actuator. For Configuration B, the overlap should be Figure Configuration B shows a linear and proportional behavior as long as the overlapping state does not change from overlapping to not overlapping within the travel range of the displaced counter electrode.The force displacement characteristic of Configuration A. The electrostatic spring rate yields a constant behavior after overcoming the effects at the initial x-position of the counter electrode, which is almost independent of the varying design parameter Figure Configuration B indicates a strong dependence on the electrode design. Figure In contrast, the force-displacement characteristic of 23, the maximum achievable displacement is usually restricted by side instability. This limit is caused by a pull-in of the electrodes at a displacement As known from comb-drive actuatorsy-direction), the corresponding electrostatic force n pairs consisting of one curved electrode and one counter electrode, the vertical force For the calculation of the electrostatic stiffness in the off-axial direction (The electrostatic stiffness Solving (9) and (8) for the proposed geometry defined in (5) results in a large term that can be simplified by a linear Taylor series at the point y-displacement. The results are plotted in Fig. y.To verify the last approximation, an FEA was carried out to simulate 23 or Reference. 24 and can be determined by solving (9) considering a constant electrode gap of In addition to the curved electrodes, the parallel plate actuators that are required for the offset compensation also contribute to the vertical electrostatic stiffness. This vertical stiffness Here, The largest possible displacement x, a possible solution for the maximal displacement yields:By inserting (10) in the last inequation and solving for x-displacements of the counter electrode by increasing the voltage, as shown in Fig. The last inequation is verified by a series of FEA simulations considering a pair of curved electrodes and a spring-based counter electrode. A simulation of the pull-in was provoked for various 11. In addition, the input stiffness 11 and on the model of the negative spring constant provided in (6), the input stiffness of a two-stage amplifier can be approximated byThe electrostatic anti-spring is mounted at the output element of the mechAMP to compensate for the high input stiffness. In a purely mechanical configuration, the input stiffness Here, The last equation also shows that the force-compensated amplifier can be used as a tuneable force sensor. Here, a force at the input of the mechAMP is converted into a displacement at the output, and the sensitivity of the force sensor is tuneable by the voltage applied at the anti-spring:For the design of the demonstrators, a mechanical amplifier with amplification ratios ofmentclass2pt{minimConfiguration A are mounted at the output of the mechAMP for each direction. Figure In total, 40 pairs of electrodes of x-direction). For this reason, we use triangular springs in a clamped-clamped configuration, as shown in Fig. 25.Highly selective guiding springs are mandatory for a large translational displacement. On the one hand, the spring provides a high stiffness mentclass2pt{minimHere, the electrostatic anti-springs are guided by triangular springs featuring 27, is shown in Fig. The force-compensated mechanical amplifiers are realized on a (100)-oriented 100 mm SOI substrate featuring a 20 µm device layer. The fabrication process, based on a concept known from refs. Figure 25).Figure The tungsten needle is used to displace the amplifier externally at the input of the amplifier using the piezo stage. The introduced force Within the characterization, we first analysed the amplification ratio for various applied voltages. As we expect, the anti-spring should not influence the amplification ratio. Based on the visual measuring concept where the input and output displacements are tracked by a microscope camera, a microsystem of version 3 with a low amplification ratio of a nominal value of 25 is used for this experiment. Figure Based on the measurements in Fig. To determine the input stiffness a shows a higher spring rate sensitivity Figure In the theoretical section, according to Eq. , we discConsidering the mechanical amplifier as a tuneable force sensor, the diagram in Fig. Figure Figure As discussed in the theoretical section, the output displacement of the mechanical amplifier is limited by side instability. In Fig. The design, modeling and characterization of an electrostatic compliant micromechanical amplifier is presented in this paper.The mechanism features 40 bidirectional actuators that allow adjustment of the input stiffness of the mechanical amplifier by applying a DC voltage. It can be shown through experiment that due to this anti-spring, the intrinsic and external stiffness caused by the required components, such as flexure hinges or guiding springs, could be drastically reduced from 422 N/m to 6.8 N/m by applying a voltage of 100 V.a and decreasing the Factor b allows large deflections of the anti-spring before pull-in. However, a steep slope of the force-displacement characteristic of the anti-spring is achieved by choosing a small value of a. The analytical approach was also confirmed through FEA simulations and experiments. Here, we have shown that the output displacements of over 60 µm are still possible at the maximum voltage of 100 V.The influence of the design parameters was analysed regarding the stiffness-to-voltage relation of the force-displacement characteristic, the side-instability and thus the maximal displacement of the anti-spring. We could show that increasing the Factor As a potential application, the mechanical amplifier can also be used as a tuneable force sensor transforming an input force into a displacement signal. We were able to show that the sensitivity of the displacement-to-force relation could be tuned by a factor of 25. Additionally, in inertial sensors such as in MEMS accelerometers or gyroscopes, the proposed microsystem can be used to amplify and adjust the sensitivity of the respective sensor.


Arterial stiffness is often increased in overweight/obese subjects before the development of hypertension. It is also one of the earliest indicators of increased cardiovascular disease risk and can be considered a good predictor of the development of subclinical cardiovascular dysfunction. Arterial stiffness is a significant prognostic factor influencing cardiovascular risk, which dietary habits can modify. Obese patients should use the caloric-restricted diet because it augments aortic distensibility, diminishes pulse wave velocity (PWV), and increases the activity of endothelial nitric oxide synthases. High intake of saturated fatty acids (SFA), trans fats, and cholesterol, typical for the Western diet, impairs endothelial function and raises brachial-ankle PWV. The replacement of SFA with monounsaturated (MUFA) or polyunsaturated fatty acids (PUFA) derived from seafood and plants diminishes the risk of arterial stiffness. The dairy product intake (excluding butter) decreases PWV in the general population. The high-sucrose diet causes toxic hyperglycemia and increases arterial stiffness. Complex carbohydrates with a low glycemic index  should be recommended to keep vascular health. The high sodium intake (>10 g/day), particularly associated with low potassium consumption, has a deleterious effect on arterial stiffness (↑ baPWV). Since vegetables and fruits are good sources of vitamins and phytochemicals, they should be recommended in patients with high PWV. Thus, the dietary recommendation to prevent arterial stiffness should be similar to the Mediterranean diet, which is rich in dairy products, plant oils, and fish, with a minimal red meat intake and five servings of fruits and vegetables daily. Currently, obesity is a serious chronic disease, which constitutes not only a health problem but also a social and economic one. The number of overweight and obese subjects is still increasing. This is why the global nature of the obesity epidemic was recognized by the WHO, in 1997. In 2022, the World Health Organization (WHO) reported that there are about 2 billion adults who are overweight, whilst 650 million are obese. It is expected that 2.7 billion adults will be overweight, and over 1 billion will be obese by 2025 if these rates do not slow down . In physiological conditions, oxidative stress markers are neutralized by antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPX) [2− reacts with nitric oxide (NO) and consequently decreases its bioavailability. In addition, the product of mentioned reaction (ONOO−) promotes the dysfunction of endothelial nitric oxide synthase (eNOS), which causes a further reduction in NO concentration [Obesity is a pathological condition, which is connected with excess calorie intake, and consequent accumulation of free fatty acids (FFA) and carbohydrates. Consequently, the increased oxidative stress markers production occurs via different mechanisms such as activation of protein kinase C (PKC), polyol and hexosamine pathways, and synthesis of superoxide anion . Among ose (GPX) . Among ose (GPX) . The accse (GPX) . Moreoventration . Increasntration . Increasntration . Enhancentration . In addintration . The prontration .It is known that arterial stiffness increases among obese and overweight individuals, especially with excess abdominal fat ,21,22 F. IncreasInterleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) are the main inflammatory factors, whose level is elevated among obese patients. IL-6 is produced by different cells such as adipocytes and macrophages, which infiltrate adipose tissue and endothelial cells, while TNF—α is primarily a product of macrophages ,24. BothIL-6 is involved in the regulation of endothelial function by improving the upregulation of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which have pro-atherogenic facilities . MoreoveIt is known that obesity, or even overweight, causes impaired insulin release, with hyperinsulinemia, in the beginning, causing the gradual worsening function of β cells of islets of Langerhans. Normal insulin metabolism plays an essential role in maintaining proper endothelial function . HyperinObesity, mainly caused by excess energy intake, especially due to a diet that is not rich in carbohydrates and a high-fructose diet, is associated with increased angiotensin II (ANG II) production by different types of adipose tissue, visceral as well as perivascular adipose tissue (PVAT) . Ang II The synthesis and release of factors derived from adipocytes by visceral as well as PVAT are impaired among obese patients. In addition to the factors mentioned above, there is an important change in the production and release of adiponectin and leptin ,43.Almabrouk et al. presented their study with mice fed a high-fat diet, and the level of adiponectin was reduced by 70% . There aThe level of leptin among obese patients is enhanced, while the synthesis of leptin by adipocytes is directly proportional to its size . Leptin The randomized, controlled study conducted on overweight and obese middle-aged and older adults showed that intentional weight loss  reduces large artery stiffness. This effect is independent of a reduction in abdominal adiposity and is associated with accelerated arterial stiffening and an increased risk of adverse cardiovascular events ,51,52,53Since arterial stiffness influences vascular ageing and is an independent predictor of CVD and related mortality, the analyses of factors that may decrease its value are a reason for scientific curiosity ,57. An iArterial stiffness is a significant prognostic factor of CVD, influenced by dietary habits. During the planning of diets, it is crucial to have adequate caloric intake, which improves multiple metabolic parameters and vascular health ,64,65,66Weight loss in overweight and obese individuals is associated with reduced arterial stiffness . Modest Many data showed that caloric CR is strictly related to reduced risk of obesity and decreased arterial stiffness. However, scientific curiosity arises with the question if there is an association between specific dietary components, including macroelements , microelements, vitamins, and some nutrients, such as polyphenols and carotenoids, on arterial stiffness. All of these nutrients may influence arterial stiffness and change endothelial function. Thus, in this article, the analysis of what kinds of dietary interventions can decrease arterial stiffness and, therefore, improve vascular health and overall cardiovascular risk is analyzed. Several studies underline that both the quantity and quality of fat intake influence the CVD risk ,68,69 ann = 1469) [n = 733) without a history of CVD. On the contrary, lower intake of SFA is correlated with persistently higher baPWV (measured at baseline at 2 and 5 years) [One of the leading factors influencing cardiovascular risk is a Western diet, rich in saturated and refined fats, and high-sucrose products . SFA are = 1469) . A diet 5 years) . Moreove5 years) . A simil5 years) .Conversely to SFA, unsaturated fatty acids have a beneficial influence on vascular health. One of the unsaturated fatty acids is MUFA (mainly oleic acid), which is present in nuts, avocados, unrefined (virgin) olive oil, safflower, and canola oil . The repIn addition to MUFA, PUFA intake is also considered beneficial for vascular health. Among PUFA, both n-6 fractions (linoleic acid in vegetable oils) and n-3 fractions (seafood and plant sources) reduce CHD risk ,78. The n = 41,578, aged 40 to 59) who were free of prior diagnosis of CVD showed that high frequency or a large amount of fish intake (eight times per week or 180 g/day) versus lowest (23 g/day) reduced risk of nonfatal coronary events [n − 6), and n-3 PUFA have a beneficial effect on vascular function. Among PUFA, the essential fatty acids eicosapentaenoic EPA (20: 5n − 3) and docosahexaenoic DHA (22: 6n − 3) reduce blood pressure and increase endothelium-dependent vasodilation in diabetic and hypertensive patients [Many studies have shown that fish consumption has a beneficial influence on myocardial infarction  and hypey events . Fish anpatients . Observapatients . Some stpatients . Moreovepatients .One of the most well-analyzed nutritional diets is the Mediterranean one. This diet has received particular scientific interest in recent years as it protects against CVD, particularly compared to a Western diet. The health benefits are related to the balanced composition of macronutrients  . The MedThe primary protein sources in the diet are meat, poultry, fish, eggs, and dairy foods. Meat and eggs contain dietary cholesterol and SFA, which deleteriously affect arterial stiffness (discuss below). n = 44) compared to the omnivore control sample  [p  =  0.073), mainly male omnivores (p  =  0.006 for the effect of gender and p = 0.294 for the effect of the eating pattern effect), suggesting that the beneficial effect of the vegetarian eating pattern may be limited in premenopausal women [The beneficial influence of a low-fat meat diet is seen mainly in studies analyzing the impact of diets typical for omnivores and vegetarians/vegans on arterial stiffness, for example, lower PWV (−8%) in healthy male vegetarians (ctively) . Similaral women .Not every type of dietary protein contained in meat reveals a detrimental effect on arterial stiffness. For example, poultry meat is rich in protein and is characterized by low fat content, a high degree of unsaturation of fatty acids, and low cholesterol levels . Its benn = 2636 subjects). Over seventeen years of observation, the highest intake of total dairy products and low-fat/fat-free dairy foods were inversely correlated with the values of systolic and diastolic blood pressure (DBP). For yogurt, each additional serving was associated with a 6% reduced risk of incident hypertension [n = 136,384 adults from 21 countries), which were observed over nine years of follow-up. That study proved that dairy consumption was associated with lower mortality risk in CVD events independently of ethnicity [A good source of protein is dairy products. Many studies underline that dairy consumption may prevent or delay the onset of hypertension and is associated with a lower risk of mortality and major CVD events ,137. Sinn = 103,256 adults) analyzed the effect of various groups of dairy products on vascular health. Surprisingly, this study shows a negative association between dairy product intake and the risk of CVD. It proves that intakes of non-fermented milk (≥ 2.5 times/day) are associated with higher all-cause mortality compared with subjects who consumed milk ≤1 time per week. However, fermented milk and cheese intake is associated with lower all-cause mortality [Dairy products not only decrease the risk of cardiovascular events and hypertension but also have a positive influence on arterial stiffness. An inverse relationship between dairy product intake and arterial stiffness measured by PWV pulse wave velocity was proved in the general population . Similarortality .n = 2512 men aged 45 to 59) analyzed cardiovascular health followed up at 5-year intervals for a mean of 22.8 years. The AIx was 1.8% lower in subjects in the highest quartiles of dairy product intake compared with the lowest (p trend = 0.021). Consumption of dairy products, excluding butter, was not detrimental to arterial stiffness and metabolic markers  [Some disinclinations in the assessment of dairy product intake on arterial stiffening can be associated with the fat content in these foods. However, the analysis of milk, cheese, cream, and butter on aortic PWV, augmentation index (Alx), and blood pressure did not confirm the detrimental effect of dairy products on CVD risk (except butter). This large cohort prospective study (esterol) . Additioesterol) . Moreoveesterol) . Anotheresterol) .The confusing data regarding the influence of dairy products on metabolic parameters and endothelial health can result from the numerous non-fat components in dairy fermented and non-fermented products revealing specific nutritional functions and thus explaining various health benefits. Active molecules present in dairy products are biologically active tripeptides derived from casein. They have antihypertensive properties, which probably result from the ability to reduce angiotensin formation. It has been suggested that casein-derived tripeptides may reduce arterial stiffness and improve endothelial function . It is wn = 1291, age range 23–85 years), which demonstrated that the 1 h postprandial glucose level is associated with increased arterial stiffness (measured by CAVI—cardio-ankle vascular index) in non-diabetic patients. Furthermore, postprandial glycemia was an independent predictor of CAVI values in men and women over 50 years of age [Arterial stiffness is affected by the quantity and quality of ingested carbohydrates, particularly simple sugars, and complex carbohydrates. Moreover, the relationship between arterial stiffness and postprandial blood glucose levels increases with age. This thesis was proved by a large Japanese study  [On the contrary, low-carbohydrate diets reduce CVD and diabetes risk not only by decreasing serum glucose and lipid level but also by improving aortic stiffness in a short time (four weeks) ,99,100. Complex carbohydrates and fibers  are the main components of dietary products with a low glycemic index (GI). Such foods impact metabolic changes and modulate insulin production ,141. Morn = 10, healthy middle-aged and older adult) [Not every simple sugar has a deleterious impact on arterial health. Recently, many studies have underlined the crucial effect of isomaltose on vascular health. Isomaltose is a naturally occurring beet disaccharide and can be commercially produced from sucrose on an industrial scale. It is used in various food and drink additives and clinical formula diets as an alternative sugar . Isomaltr adult) . Furtherr adult) . Thus, ir adult) ,103,144.n = 36,324 subjects, aged 49.10 ± 12.57 years) analyzed the influence of various amounts of sodium intake  on arterial stiffness. The high sodium intake (>10 g/day) revealed a deleterious effect on arterial stiffness (baPWV ≥ 1400 cm/s) [A critical dietary factor modulating arterial stiffness is dietary sodium intake. A high-salt diet leads to hypertension and increases incidences of cardiovascular disease ,145,146.00 cm/s) . Convers00 cm/s) . The ben00 cm/s) . Sodium influences vascular health  in both the normotensive and hypertensive groups of patients. The data regarding normotensive subjects have shown that high-sodium meal increases the AIx  and raisSince the blood sodium and potassium concentrations influence blood pressure, the analysis of sodium intake is usually performed in the context of potassium supplementation. The available data regarding the role of potassium in arterial stiffness are inconsistent. Data for high potassium supplementation /d from fruit and vegetables) do not show changes in arterial stiffness and endothelial function compared to a low-potassium diet used in the early stages of hypertension . Some daSince both macroelements (sodium and potassium) influence blood pressure and arterial stiffness, some data suggest that their ratio can be used as a reliable marker of vascular health. For example, a cross-sectional study by Garcia-Ortiz et al. showed that the sodium-to-potassium intake ratio is associated with the aortic AIx and arterial stiffness parameters (including PWV) . Some daThe influence of sodium on endothelial function is strictly related to the ability of sodium elimination from urine. The study by Del Giorno has shown that low daytime urinary sodium excretion is associated with increased arterial stiffness and central blood pressure . AnalysiHypertensive patients using high-sodium and low-potassium diet are encouraged to implement the DASH diet (Dietary Approaches to Stop hypertension). Such diets can also have a beneficial influence on arterial stiffness. DASH diet is rich in vegetables, fruits, and low-fat dairy products, which results in low sodium intake. The DASH diet reduces blood pressure in subjects with and without hypertension, regardless of race and gender. Compared to the control diet, which is typical for the United States, and is characterized by a high sodium level, the DASH diet with a low sodium amount caused a lower mean SBP of 7.1 mmHg in normotensive participants and a decrease of approximately 11.5 mmHg in hypertensive patients with SBP . TherefoSince supplementation of vitamins can improve endothelial function, many studies recently analyzed the influence of these molecules on vascular health. Intake of ADEC vitamins decreases inflammatory and oxidative stress processes, which are deleterious for endothelial function and arterial wall changes  . Antioxin = 1318 participants in the orally supplemented vitamin group vs. n = 1115 subjects in the placebo group) showed no statistically significant effects on arterial stiffness . However, if oral vitamin supplementation was longer than 12 weeks, vitamin D3 showed a significant reduction in central arterial stiffness, compared with the placebo (−60.0% m/s). Other studies confirm the beneficial effect of vitamin D on cardiovascular risk. Both forms of vitamin D, circulating ergocalciferol (25-hydroxyvitamin) and its active form , influence endothelial function via endothelial vitamin D receptors (VDR) and enzymes converting circulating vitamin D to the active form. In vitamin D deficiency, an increased risk of CVD and arterial stiffness is observed [Recently available data on vitamin influence on endothelial function (strictly related to the stiffness of the artery) is controversial. A meta-analysis by Saz-Lara et al.   ,160. TheRecent data also underline the potential roles of folate and/or related B vitamins in protecting against CVD , certain cancers, cognitive impairment, and osteoporosis . NicotinThe intake of fruits and vegetables has a beneficial influence on arterial stiffness and supports the recommendation to consume more than five servings of fruits and vegetables per day, reducing cardiovascular risk, which is partially related to vitamin consumption . The proPhytochemicals include a large group of active compounds with antioxidative, antiproliferative, anti-inflammatory, and inhibitory angiogenesis molecules important in preventing chronic diseases. They reduce neointimal thickening by inhibiting smooth muscle cell proliferation, thus improving endothelium-dependent vasorelaxation. Phytochemicals also modulate the bioavailability of nitric oxide and voltage-gated ion channels . The maiPolyphenols are the natural components of various fruits, vegetables, cereals, and beverages, which may reduce arterial stiffness. About 100 g of fresh grapes, apples, pears, cherries, and berries deliver up to 200–300 mg of polyphenols. They are also present in red wine, tea, and coffee and in smaller amounts in cereals, dry legumes, and chocolate ,174. FlaOther nutrients that seem to benefit arterial stiffness are phytoestrogens ,183. Phyn = 264, 31–75 years), which showed a significant decrease in baPWV with increased lycopene concentration [n = 299) after considering confounding factors such as blood pressure, insulin resistance, and oxidative stress [n = 255, aged 40–65 years) showed that a relatively high daily consumption of tomato products (32–50 mg lycopene/day) or lycopene supplements (10 mg/day) was ineffective in reducing conventional cardiovascular risk markers and arterial stiffness in middle-aged individuals [Similarly to flavonoids, beneficial antioxidative effects have carotenoids. They reveal antiatherogenic properties by reducing inflammation and ROS formation within the arterial wall. Carotenoids with many conjugated double bonds demonstrate their antioxidant potential. They also improve endothelial function  and decrntration . A simile stress . On the ividuals . Thus, tSince an ageing society characterizes the general population, it is crucial to control the progression of arterial stiffness using a well-balanced diet. Such a diet should contain adequate energy intake to maintain proper body mass. In the case of overweight and obesity, caloric restriction should be considered. A well-balanced diet is one of the most important recommendations for preventing arterial stiffens. Such a diet should contain a proper quantity and quality of protein, fat, and carbohydrate . Two diets can have beneficial effects on vascular health—the DASH diet and the Mediterranean diet. Both diets are rich in vegetables, fruits, low-fat dairy products, and minimal sodium intake. They are widely recommended to diminish or prevent hypertension and cardiovascular events and minimize the risk of arterial stiffness; furthermore, these types of diets decrease inflammation, improve endothelial function, and increase flow-mediated dilatation ,153,175.Adequate fat intake should include a low amount of trans and saturated fats, possibly replacing them with MUFA and PUFA . FermentSince endothelial dysfunction and increased arterial stiffness are predictors of CVD, a well-balanced diet should be the first step to maintaining vascular health. This review gathers the main dietary recommendations supported by multiple studies. It underlines the role of nutritional habits in overweight or obesity and suggests healthy behavior which can help reduce body mass and improve endothelial function. Striving for a correct body weight through a negative energy balance should be the first element of prophylaxis in excessive body mass and arterial stiffness prevention. Low-fat and high-fiber products (low-energy and food characterized by low GI index) in the diet are crucial for proper body mass achievement. Unfortunately, the Western diet  is the leading cause of obesity and arterial stiffness. High-fat and high-sucrose diets typical for quickly available food not only increase body mass but also have harmful effects on vascular health. Replacing red meat with fish, margarine with olive oils, and sweets with vegetables can be the first step in decreasing adiposity. In addition, normalization of the metabolic state by weight loss returns arterial stiffness and blood pressure to normal. Patients (independently of co-existed diseases) should know the basic dietary recommendations to maintain general and vascular health. The role of nutritional education, in this case, is invaluable. Heightened awareness of the adverse consequences of obesity and obesity-related complications  should prompt healthcare providers to institute early and aggressive lifestyle interventions in overweight and obese patients. Thus, there is a need for the development of early detection and prevention programs to mitigate this potentially serious health problem.Future research should examine arterial stiffness and its influence on cardiometabolic health outcomes in various populations characterized by a specific age, body mass (overweight and obesity), and co-morbidities . Such data can provide valuable insights into the role of particular nutrients and eating patterns on arterial stiffness and cardiometabolic health. The not-fully defined role of specific products in arterial stiffness  should be carefully analyzed. Considering the epidemic incidence of obesity worldwide, caused mainly due to excessive consumption of a high-energy diet, arterial stiffness could represent a novel therapeutic target to prevent obesity-associated cardiovascular complications. Początek formularza.


Prolonged warm ischemia time (WIT) and cold ischemia time (CIT) are independently associated with post-transplant graft failure; their combined impact has not been previously studied. We explored the effect of combined WIT/CIT on all-cause graft failure following kidney transplantation.The Scientific Registry of Transplant Recipients was used to identify kidney transplant recipients from January 2000 to March 2015 (after which WIT was no longer separately reported), and patients were followed until September 2017. A combined WIT/CIT variable  was separately derived for live and deceased donor recipients using cubic splines; for live donor recipients, the reference group was WIT 10 to <23 minutes and CIT >0 to <0.42 hours, and for deceased donor recipients the WIT was 10 to <25 minutes and CIT 1 to <7.75 hours. The adjusted association between combined WIT/CIT and all-cause graft failure (including death) was analyzed using Cox regression. Secondary outcomes included delayed graft function (DGF).A total of 137 125 recipients were included. For live donor recipients, patients with prolonged WIT/CIT (60 to ≤120 minutes/3.04 to ≤24 hours) had the highest adjusted hazard ratio (HR) for graft failure . For deceased donor recipients, a WIT/CIT of 63 to ≤120 minutes/28 to ≤48 hours was associated with an adjusted HR of 1.35 (95% CI = 1.16-1.58). Prolonged WIT/CIT was also associated with DGF for both groups although the impact was more driven by CIT.Combined WIT/CIT is associated with graft loss following transplantation. Acknowledging that these are separate variables with different determinants, we emphasize the importance of capturing WIT and CIT independently. Furthermore, efforts to reduce WIT and CIT should be prioritized. Both prolonged WIT and CIT have been shown to independently impact kidney allograft survival. Each additional hour of CIT increases the risk of graft failure and mortality. In addition, we previously showed that prolonged WIT is associated with delayed graft function (DGF), graft failure and death after transplantation.Kidney transplantation is the optimal form of kidney replacement therapy and is associated with improved survival and quality of life compared with dialysis. Therefore, improving kidney organ survival after transplantation is of paramount importance. Minimizing both warm and cold ischemic injury is an areas of focus for the international transplant community. Changes to organ allocation and distribution (as evident in the United States) may lead to longer CIT in both live and deceased donor recipients.10 Therefore, having a better understanding of the impact of WIT and CIT on post-transplant outcomes is critical, as both of these are potentially modifiable.1114Although WIT is a well-known risk factor for patient and organ survival after transplantation, as of 2015, WIT is not a mandatory variable that is collected in the United States Organ Network (UNOS) database. Furthermore, systematic capture of WIT is not prioritized in other transplant registries.Therefore, the objective of this study was to examine the combined impact of WIT and CIT on (1) death or graft failure and (2) DGF in a cohort of kidney transplant recipients. We hypothesized that combined prolonged warm and cold ischemia would be associated with a higher risk of all-cause graft failure and a higher risk of DGF following kidney transplantation.216 The article was prepared according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines .We analyzed a national cohort of kidney transplant recipients from January 2000 to March 2015. Patients were followed from the date of transplantation to death, graft failure, end of follow-up, or the last date of follow-up . The Scientific Registry of Transplant Recipients (SRTR) was used to identify patients who underwent renal transplantation during the period of follow-up. The SRTR data system includes data on all donors, waitlisted candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplant Network (OPTN). The Health Resources and Services Administration, US Department of Health and Human Services, provides oversight to the activities of the OPTN and SRTR contractors. We included only those with complete data for WIT and CIT and excluded patients under 18, those who received multiple organs, or those who received sequential transplants as has been done in previous studies exploring the independent impact of WIT and CIT on outcomes.19 As per the SRTR, CIT was defined as the number of hours that the kidney organ was in cold storage beginning from donor kidney cross-clamp. Warm ischemia time was defined as the time in minutes from removal of the kidney from cold storage to reperfusion with warm blood , inclusive of surgical anastomosis time.Our primary exposure variable was derived from the combination of WIT and CIT. Although both variables were included in the SRTR during the time period of cohort inclusion, WIT was no longer separately reported as of end of March 2015; rather, it was combined with CIT and reported as a single value. For deceased donor recipients, CITs of less than 1 hour and greater than 48 hours were removed, and for live donor recipients, CITs of 0 hours and greater than 24 hours were removed. Subsequent to data exclusions, to create a composite variable that combined both WIT and CIT, CIT and WIT were categorized primarily using a data-driven approach. For the data-driven approach, we used cubic splines that have been previously used to categorize continuous predictors in multivariable modeling. Cubic splines produce a series of knots, or end points, that best approximate a function. This method was chosen over other categorization methods, such as quartiles, as it more optimally categorizes continuous data. For deceased donor recipients, CIT was categorized as 1 to <7.75, 7.75 to <16.43, 16.43 to <28, 28 to ≤48 hours and WIT as 10 to <25, 25 to <38, 38 to <63, and 63 to ≤120 minutes. For living donor recipients, CIT was categorized as >0 to <0.42, 0.42 to <1, 1 to <3.04, 3.04 to ≤24 hours and WIT as 10 to <23, 23 to <35, 35 to <60, 60 to ≤120 minutes. This led to a single 16-level categorical variable combining both WIT and CIT separately for each of live and deceased donor recipients.For both WIT and CIT, outliers and potentially erroneous values were removed as has been done in prior literature. Specifically, WITs of less than 10 minutes and greater than 120 minutes were excluded from the analysis due to the possibility of data entry errors or implausible values.21Potential confounders of interest were collected from the SRTR database on the basis of their perceived association with the exposure (WIT/CIT) and outcomes of interest. These included recipient characteristics , donor characteristics , transplant/surgical characteristics (donor transplant side and expanded criteria donor and donation after circulatory death for deceased donors), and immunologic characteristics (human leukocyte antigen mismatch and peak panel reactive antibody).The primary outcome of interest was a composite of death and graft failure . Graft failure was defined as a permanent return to dialysis or pre-emptive retransplantation. In a prespecified secondary analysis, we analyzed each component of the primary outcome separately . Delayed graft function was also evaluated as a secondary outcome and defined as the need for dialysis in the first week post-transplantation.21 In this analysis, for recipients of deceased and living donors, WIT was divided into categories of 10 to <30, 30 to <60, and 60 to ≤120 minutes. As CIT is generally longer for deceased donor recipients, CIT for deceased donors was categorized as 1 to <12, 12 to <24, and 24 to ≤48 hours and for living donors as >0 to <1, 1 to <3, and 3 to ≤24 hours. (2) The impact of combined WIT/CIT on the primary and secondary outcome (DGF) was analyzed inclusive of all values of WIT/CIT . (3) To remove the potential impact of prolonged ischemia time during the DCD withdrawal process (which was not robustly available in this data set), the impact of combined WIT/CIT on the primary outcome was analyzed among deceased donor recipients but excluding DCD recipients. (4) To address missing data and acknowledging the primary analytic approach used case-wise deletion, the primary analysis was repeated using multiple imputation with chained equations. Variables used to impute missing values included donor characteristics: race, body mass index (BMI), history of diabetes mellitus, hepatitis C positive, hypertension; recipient characteristics: sex, race, BMI, previous kidney transplant, cause of end-stage renal disease, dialysis vintage; and immunologic characteristics: number of human leukocyte antigen (HLA) mismatches, panel-reactive antibody (PRA) category. The impact of combined WIT/CIT on all-cause graft failure was evaluated with the data set following the imputation. In addition to sensitivity analyses, the impact of combined WIT/CIT on all-cause graft failure was evaluated across prespecified subgroups of interest including expanded versus standard criteria donor status (deceased donor recipients only), donation after circulatory death (deceased donor recipients only), age (using a threshold of ≥65), sensitization (using a panel reactive antibody threshold of >80), and elevated BMI (using a threshold of >35 kg/m2). For subgroup analyses, combined WIT/CIT was treated as a binary variable  and separately analyzed for each of live and deceased donor recipients (using the data driven approach). All statistical analyses were performed using Stata version 16.1 .Baseline characteristics were reported separately for live and deceased donor kidney transplant recipients. For all baseline characteristics, categorical variables were reported as counts and percentages and continuous variables were displayed as means and standard deviations or medians with Q1-Q3 for non-normally distributed continuous variables. The WIT and CIT for live and deceased donors were graphically displayed using histograms. Time to all-cause graft failure for each category of WIT/CIT was analyzed using multivariable Cox proportional hazard models; the association between WIT/CIT and graft failure was reported using relative hazard ratio (HR) with 95% confidence intervals (CIs). For all models, the reference group was the shortest combination of WIT/CIT. Missingness was handled using case-wise deletion. For all Cox models, proportionality was assessed using visual examination of log-log plots. For the primary analysis, we adjusted for donor factors, recipient factors, and surgical and immunologic factors noted above. For DGF, we used logistic regression and reported the odds ratios (ORs) and 95% CIs for each category of WIT/CIT, adjusting for the same variables. In addition to the primary analysis, we performed 4 additional sensitivity analyses to test the robustness of our primary finding. (1) the effect of combined WIT/CIT on the primary outcome was analyzed using a clinical approach by categorizing CIT and WIT into short, medium, and long durations using thresholds defined by the available literature.Supplemental Table S2.The final study cohort included 137 125 patients, consisting of 83 247 (61%) deceased donor recipients and 38 020 (39%) live donor recipients . BaselinSupplemental Table S2). For deceased donor recipients, median (IQR) WIT was 36 (29-47) minutes and median (IQR) CIT was 17 (11.5-23) hours  is noted in For live donor recipients, median (interquartile range [IQR]) WIT was 33 (25-45) minutes and median (IQR) CIT was 1 (0.95 to 2) hours (3) hours . DistribSupplemental Table S3). There was a graded increase in the point estimate for graft failure with each increase in prolonged WIT/CIT, but confidence intervals overlapped. Among live donor recipients, the risk of death/graft failure was 61% higher for those with a WIT of 60 to ≤120 minutes and CIT of 3.04 to ≤24 hours  compared with the reference category . A graded increase in the point estimate for graft failure was noted for those in the highest category of WIT with each increase in CIT, although confidence intervals overlapped. The impact of combined WIT/CIT on each subcomponent of the primary analysis is shown in Supplemental Table S4. Among deceased donor recipients, the highest point estimate for death with graft function was found in those with prolonged WIT/CIT. Among live donor recipients, the findings were inconsistent for both death with graft function and death-censored graft failure.Among deceased and live donor recipients, there were a total of 38 755 and 13 113 primary events, respectively. Overall, cumulative time at risk was 784 631 patient years (504 013 for deceased donor recipients and 280 618 for live donor recipients), and median follow-up time was 5.74 (3.14-8.80) and 4.90 (2.86-7.85) for deceased and live donor recipients, respectively. For deceased donor recipients, compared with the reference category , those with both prolonged WIT (63 to ≤120 mins) and prolonged CIT (28 to ≤48 hours) had a 35% increase in the adjusted relative hazard for all-cause graft loss , irrespective of the WIT; the highest risk  was observed for those with combined short WIT (10 to <25 minutes) and long CIT (28 to ≤48 hours). For live donor recipients, the relationship between prolonged WIT/CIT was not as consistent; however, the highest risk  was observed among those with the longest WIT/CIT (WIT 60 to ≤120 minutes and CIT 3.04 to ≤24 hours).The risk of DGF for combined WIT/CIT is noted in Supplemental Table S6). Among deceased donor recipients, the adjusted HR for death/graft failure for a WIT of 60 to ≤120 minutes and CIT of 24 to ≤48 hours was 1.26 (95% CI = 1.17-1.37). Among live donor recipients, the risk of graft loss for combined WIT/CIT was only significant for those in the highest category of WIT (60 to ≤120 minutes) and CIT . When including all values of WIT/CIT , results were similar for those with prolonged WIT/CIT; however, the risk was also high for some categories of short WIT . The impact of removing DCD recipients yielded similar results to the primary analysis, wherein a graded response was observed particularly among the longest categories of WIT/CIT . Similarly, the implementation of multiple imputation using chained equations provided similar results to the analysis using case-wise deletion , although the graded increase in risk of CIT for each incrementally higher WIT category was not as evident, particularly for live donor recipients using the data-driven approach.The results were generally similar using clinical categories to define combined WIT/CIT  across subgroups of interest . A potenIn this study, we identified that prolonged WIT and CIT were associated with an increased risk of graft failure and death after transplantation. This association was largely consistent using two different approaches to creating a combined WIT/CIT variable, and although the magnitude of the effect differed and CIs overlapped, it was present among live and deceased donor recipients after adjustment for confounding variables. and a principal factor leading to DGF.23 It has previously been shown that each additional hour of CIT is associated with an increased risk of graft failure and mortality. Similarly, Hernandez et al demonstrated that each 5-hour increase of CIT was associated with a 20% increase of death-censored graft loss. In this study, we demonstrated an association with both graft loss and DGF. Regarding DGF, among deceased donors, the effect was more related to CIT wherein WIT showed minimal impact on DGF when CIT was prolonged. The highest point estimates for DGF were noted even in those with short WIT, suggesting that the mechanisms causing DGF may occur prior to WIT. It is for reasons like these that we emphasize the importance of capturing WIT independently of CIT.Our results are consistent with previous work (including our own) indicating that separately considered, prolonged WIT and CIT are associated with adverse outcomes. Prolonged CIT has been shown to be an independent predictor of graft survival24 The impact of prolonged WIT on long-term graft survival has also been shown in cohorts outside of the United States, that is, in both Japan and the Netherlands.25 Irish and colleagues were among the first to identify the impact of CIT on DGF, although they did not include WIT in their risk prediction nomogram. Although these relationships have been established, our study is the first, to our knowledge, to examine the combined impact of WIT and CIT on both surrogate (DGF) and end outcomes of death and graft failure, using both a data-driven approach and clinical approach based on literature-informed thresholds.Our previous work with data from the United States demonstrated that prolonged WIT was associated with an increased relative hazard of death and graft failure.; however, the exact mechanisms responsible for this damage are still not fully understood. Some suggested mechanisms for cold ischemia include hypoperfusion, induced hypoxic injuries, and ultimately ischemia-reperfusion injury,13 whereas for warm ischemia, hemodynamic stress, cellular injury, and activation of inflammatory mediators have all been implicated.29 While the reason underpinning the higher combined effect of both WIT and CIT remains to be determined, we speculate that the combination of prolonged WIT/CIT results in a “two-hit” model of injury to the graft, wherein grafts exposed to both prolonged WIT and CIT time may be more susceptible due to cumulative damage through multiple pathways. Beyond the pathophysiological impact, we must also consider that the impact of prolonged WIT/CIT may be secondary to additional factors not captured within the data set. These factors may include quality of the graft, recipient anatomy or body habitus, or use of ischemia-reducing strategies such as cooling blankets, perfusion machines (hypothermic machine), or other innovative solutions. Nonetheless, the impact of combined WIT/CIT seemed to persist even for live donor recipients, suggesting that this risk is present even in higher quality and more resilient organs.It has been shown that prolonged CIT is hazardous to long-term graft survival31 which can impact patient complications and subsequently lead to increased mortality risk. Finally, there are unmeasured recipient characteristics that may prolong CIT and WIT, such as the degree of frailty or additional comorbidities, which may contribute to a heightened mortality risk. For example, recipient frailty may influence donor selection, leading to prolonged CIT, or may lead to prolonged WIT as a result of increased surgical time in the setting of a patient with underlying comorbidities or health deficits.One interesting finding in this study was that there was an association between increasing WIT/CIT and the outcome of death with graft function. We consider many possible reasons for this observation. First, as chronic kidney disease is known to be independently associated with mortality risk, the impact of WIT/CIT on kidney function, even to a small degree, may pose downstream effects on survival. Second, both WIT and CIT have been shown to induce inflammation,3335While finding ways to reduce CIT seems intuitive, due to the nature of the solid organ sharing program in the United States, shortening CIT may not be possible, especially if the focus is on maintaining equitable access to organs. If the DSA is quite large, it may be impossible to reduce CIT times. Our previous work has demonstrated that efforts to reduce HLA mismatches are important, but the benefits are not as clear if the duration of CIT exceeds 20 hours. As such, CIT duration should be a consideration when transporting organs across large DSAs. Furthermore, efforts to minimize cold time with hypothermic machine perfusion have been shown to reduce the rates of DGF (from deceased donors) and improve short-term outcomes.37 If CIT is not easily modifiable, identifying novel ways to reduce WIT  may be another consideration. These innovative approaches include minimizing rewarming during anastomosis through devices such as cooling jackets or devices that prevent rewarming of the kidney during anastomosis. Although WIT may be shortened by reducing anastomosis time, it is likely that longer anastomosis times  may not be avoidable. Similar to CIT, there are unmodifiable factors associated with prolonged WIT, including recipient BMI and kidney type . Furthermore, as suggested by prior literature, speeding up the time of surgical anastomosis may also be associated with additional risk.At present, the Organ Procurement and Transplantation Network (OPTN) is responsible for organ allocation in the United States. The kidney allocation system considers several factors such as the calculated panel reactive antibody (CPRA), estimated post-transplant survival (EPTS) score, HLA and ABDR mismatches, recipient waiting time, and distance within the donation service area (DSA).Of importance, prolonged WIT/CIT  was still associated with a higher relative hazard of all-cause graft loss among live donor recipients. It is acknowledged that CIT is typically shorter in live donor recipients. While CIT may not be equitably modified for deceased donor recipients, concerted efforts to keep CIT short for live donor recipients would be supported by the results of our study. It should be emphasized though that the impact of prolonged CIT on the composite outcome was only observed among those with the longest WIT, something that cannot necessarily be anticipated in advance. In addition, it has been shown that DGF was reduced particularly among highly sensitized patients with shorter CIT. In another study, optimizing the timing of pretransplant HLA testing leads to a reduction in CIT, and the effect on DGF was more pronounced among those who were highly sensitized (PRA >80%). Thus, a more detailed analysis of the impact on prolonged WIT/CIT among sensitized patients would be of interest for future study, and sensitized patients may be most likely to benefit from concerted efforts to lower CIT/WIT, appreciating that ensuring access to organs for sensitized patients through national sharing may limit the ability to shorten CIT without reducing the donor pool for a sensitized recipient. However, it is important to appreciate that the interaction P value was only borderline significant, and thus there was a risk of a type 1 error . Therefore, further analysis into the impact of sensitization and intersection of prolonged WIT/CIT and development of donor specific antibodies would be of interest for future study.While the impact of WIT/CIT on graft failure was not modified by a number of different factors, we did identify that patients who were highly sensitized and had prolonged WIT/CIT were at a very high risk of graft failure with an adjusted relative hazard of 2.55 . It has  the concept of functional WIT and nuances of data recording remain important considerations for future contemporary work. Moreover, data for transplantation surgical complexity, the presence of learners, skill of the surgeon, and use of additional devices or technology were not recorded. These factors can impact the duration of surgery and may contribute to outcomes. Second, the dataset contained variables with considerable missingness, such as whether kidneys were placed on pump perfusion, which were not robust enough to include in our analyses. Usage of pump perfusion as an organ preservation technique has become widespread, but accurate data on the use of these pumps were not available in our study. Kidneys that have been placed on pump perfusion have been shown to reduce DGF and as such would have been an important contribution to our study. Third, there is a question surrounding miscoded or erroneous values especially at extreme values. To account for this, we removed very short and very long times in our primary analysis, leading to the exclusion of a large number of live and deceased donor recipients. While this was a limitation, we did demonstrate similar results when all data were included. We do acknowledge that while point estimates suggested the highest risk of death/graft failure for combined WIT/CIT, CIs were wide and overlapping. Therefore, it is possible that statistically significant differences in the incremental increase in risk would not have been observed in an even larger cohort. Finally, we acknowledge a potential reporting bias due to missing WIT and CIT as well as the potential for unmeasured confounding variables that may alter conclusions.Our study had many strengths. The size of the data set allowed for adjustment of many donor and recipient factors and improved generalizability. Furthermore, we demonstrated robustness of our findings through consistent results using 2 different approaches to categorizing WIT/CIT, sensitivity analyses, and key subgroups of interest. However, there were limitations to our study. First, in this administrative data set, we did not have access to some aspects of the transplantation. For example, the data set did not contain information surrounding donor warm time during organ retrieval or direct temperature assessments of the kidney. These datapoints would have been of value to our analyses. Recordings of WIT can be unreliable and a surrogate marker such as direct temperature assessment would have been valuable to complement WIT. In addition, we recognize that WIT may be impacted by dynamic elements surrounding the withdrawal for DCD donors which were unavailable within the data set. As usage of DCD kidneys continues to increase,In conclusion, we demonstrated that combined WIT/CIT is associated with all-cause graft failure and DGF following kidney transplantation. Acknowledging that both WIT and CIT are potentially modifiable, efforts should be made to identify those at highest risk, to reduce WIT where feasible, and to reduce CIT (without compromising efforts at equitable distribution of organs). Strategies to reduce WIT/CIT or reduce the consequences of injury in those with prolonged WIT/CIT should continue to be prioritized for future research.Click here for additional data file.Supplemental material, sj-docx-1-cjk-10.1177_20543581231178960 for The Impact of Combined Warm and Cold Ischemia Time on Post-transplant Outcomes by Martha E. Foley, Amanda J. Vinson, Thomas A. A. Skinner, Bryce A. Kiberd and Karthik K. Tennankore in Canadian Journal of Kidney Health and Disease