We aimed to develop dose–response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9–13.7]. MHD was not associated with HF risk overall . In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7–21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m2 (IQR 240–319). A dose‐dependent increase was observed after anthracycline without trastuzumab . After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1–110.1) compared to no chemotherapy.A case–control study was performed within a cohort of breast cancer survivors treated during 1980–2009. Cases (In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies. Radiotherapy, anthracyclines and trastuzumab are commonly used treatments for breast cancer (BC) and have all been associated with an increased heart failure (HF) risk.For anthracyclines there is strong evidence that HF risk increases with increasing cumulative dose.In this study we evaluated associations between radiation MHD and HF, and between anthracycline dose and HF. We also assessed HF associations with trastuzumab and for endocrine therapy.MethodsA nested case–control study was performed within a Dutch cohort of long‐term BC survivors treated during 1970–2009. The cohort was identified through hospital‐based registries at the Netherlands Cancer Institute, Amsterdam and the Erasmus MC Cancer Institute, Rotterdam. Details of the data collection procedures for the patient cohort have been published previously,Eligibility criteria for cases and controls were: (i) a diagnosis of BC stage I–IIIa between 1976 and 2009, (ii) age at BC diagnosis ≤65 years, (iii) no distant metastasis and no diagnosis of CVD that could have caused HF before cut‐off date , (iv) no BC recurrence treated with radiotherapy, and (v) no thoracic radiotherapy for second malignancies other than primary BC before cut‐off date. (Thoracic) radiotherapy for recurrences or second malignancies was an exclusion criterion because MHD was not available for these regimens. Chemotherapy and/or endocrine therapy for a second malignancy or recurrence were allowed and taken into account in the total cumulative dose of specific drugs.MethodsTo include all cases with left ventricular systolic dysfunction, HF was defined as either dilated cardiomyopathy or HF with reduced ejection fraction (HFrEF) with ejection fraction (EF) <50%TableEligibility of each individual case was discussed  taking into account all cardiovascular measurements and information, and blinded as to BC treatment. In total, 342 HF cases were identified, 102 were included, while 240 were excluded based on the eligibility criteria , and body mass index (BMI). Radiation charts were photocopied.MethodsTable5 to V25) were estimated for each woman in the study using the total dose received as recorded from each individual radiotherapy chart and the dose–volume histogram of the regimen received.A ‘typical CT‐scan’ was used to estimate cardiac doses retrospectively for each woman in the study (online supplementary 2) for patients receiving epirubicin was estimated using a conversion factor of 0.55, i.e. 50 mg/m2 doxorubicin was considered equivalent to 90 mg/m2 epirubicin. Four mutually exclusive treatment categories were considered for endocrine therapy: no endocrine therapy, tamoxifen, tamoxifen and aromatase inhibitor, and aromatase inhibitor only. Endocrine therapy was only considered if it started ≥3 months before HF diagnosis/cut‐off date.Chemotherapy was categorized into mutually exclusive treatment groups: no chemotherapy, cyclophosphamide, methotrexate, and 5‐fluorouracil‐like regimens, anthracycline‐based chemotherapy, anthracyclines plus subsequent trastuzumab, and other type of chemotherapy/unknown type. Cumulative isotoxic doxorubicin dose (mg/mm(1 + βd) where d is MHD/doxorubicin equivalent anthracycline dose for individual patients, Km is a constant specific to each matched set, and β is excess rate ratio  per unit increase in dose. Modelled cumulative HF incidences were estimated from the RRs together with the cumulative HF risk for the entire cohort. Analyses were performed using Stata  and Epicure  statistical software.Rate ratios (RRs) for HF were estimated using logistic regression conditional on the matching variables, i.e. age at BC diagnosis , year of BC diagnosis , and follow‐up duration . Confidence intervals (CIs) for categorical exposure variables were estimated for each category, including the reference category, from the amount of information in that category.TableTableTableTableIn 102 cases of HF, the median age at BC diagnosis was 51 years (TableTableTableP = 0.06). Restricting analyses to patients without second malignancies did not materially affect any of the results  was 3.3 (95% CI 1.5–7.2) while for patients with a median cumulative anthracycline dose of 300 mg/m2 (IQR 252–360) the RR was 8.6 (95% CI 4.7–15.6). A linear dose–response relationship was observed, with HF rate increasing by 1.5% per mg/m2 anthracycline dose (95% CI 0.5–4.1)  for MHD 2–9 Gy and 0.7 (95% CI 0.46–1.2) for ≥10 Gy MHD (Table20), the HF RR was 5.7 (95%CI 1.7–19.4) relative to women with V20 <10%. Also, in patients with 10–19% of the heart exposed to 25 Gy (V25) and 8 cases with V25 ≥20%, HF RRs were 4.1 (95% CI 1.0–15.9) and 7.8 (95% CI 1.8–34.6), respectively, relative to baseline (V25 <10%).Considering radiation dose–volume parameters in patients treated with anthracyclines without trastuzumab, there was no increased HF risk in patients according to increasing volume of the heart receiving 5 or 10 Gy Table. However2) had an increased HF rate compared to women with a BMI <25 kg/m2  and that perimenopausal women had an increased rate compared to premenopausal women  , the HF rate was significantly increased relative to other women whose V20 was <10%, suggesting that anthracycline‐related cardiotoxicity may be exacerbated by irradiating a large volume of the heart to a high dose. This latter finding is, however, based on only 17 patients, and so needs confirmation in other studies. Although our study included only 24 patients treated with trastuzumab, a strongly increased HF risk was observed for patients receiving trastuzumab compared with those who did not receive it. There was a borderline significant association between treatment with aromatase inhibitors and HF rate, based on 13 patients, but no significant increases associated with other types of endocrine therapy.This is the first study to assess the relationships between radiation dose to the heart, anthracycline dose and the risk of subsequent HF in women treated for early BC. There was no significant association between MHD and HF rate or between mean left ventricle dose and HF rate. In contrast, there was a strong, dose‐dependent, relation between HF rate and anthracycline dose. The rate was increased nearly nine‐fold for patients who received a cumulative dose of >240 mg/mIn the Netherlands, as in many countries, national BC guidelines recommend that women at high BC recurrence risk should be considered for treatment with anthracycline‐based chemotherapy and, if they are HER2 positive, with 1 year of trastuzumab. Our results are, therefore, particularly relevant to women at high risk of recurrence. It is, however, important to note that HF rates in the general population of women in the age range included in the current study are quite low.et al.The time between BC diagnosis and HF diagnosis was much shorter in cases treated with trastuzumab than in cases treated with anthracyclines but not trastuzumab. This difference occurred despite exclusion of reversible treatment‐related HF cases occurring within 1 year of treatment. The short latency between trastuzumab exposure and development of HF has been reported in large randomized trials in which trastuzumab‐related HF developed during or a few months after treatment and recovered within 6 years of stopping trastuzumab in >60% of patients.et al.The radiotherapy results in this nested case–control study differ somewhat from those reported in our cohort study,et al.http://www.oncoline.nl).The increased HF rate observed for aromatase inhibitor use only is intriguing, but should interpreted with caution as we were unable to stratify our analyses for menopausal status due to limited patient numbers (these findings were based on 13 patients). Women treated with aromatase inhibitors only are generally postmenopausal and may have, due to age and menopausal status, a worse cardiovascular risk profile, irrespective of type of endocrine therapy. However, there was no evidence that menopausal status was a confounder of the relationship between aromatase inhibitors and HF (data not shown). A number of studies have suggested that aromatase inhibitors may increase the HF risk.Strengths of our study include comprehensive data collection from medical files, including detailed treatment information, with individual cumulative anthracycline dose and estimated individual patient radiation MHD, mean left ventricle dose, and dose–volume parameters. HF diagnoses were based on information from both a general practitioner and a cardiologist. Information on the presence of cardiovascular risk factors at BC diagnosis was collected. The strict exclusion criteria that we applied with regard to other cancer treatments and history of clinically significant CVD eliminated their influence on the risk estimates. Exclusion of these cases, however, also means that it was not possible to assess the effect of BC treatments on HF rates in patients with a history of CVD before HF diagnosis. Furthermore, patient numbers in this study were too small to assess interactions between cardiotoxic treatment and cardiovascular risk factors or menopausal status. Another potential limitation is the inaccurate registration of duration of endocrine treatment in the medical files, and the incompleteness of detailed cardiac information, such as EF measurements.In conclusion, our results show a clear dose‐dependent increase in HF risk after anthracycline‐based chemotherapy. In the absence of anthracycline‐based chemotherapy, our data suggest that modern BC radiotherapy does not increase HF risk. HF risks associated with high doses to the heart (i.e. MHDs exceeding 10 Gy or large volumes of the heart exposed to ≥20 Gy) in patients receiving anthracycline‐based chemotherapy require further studies. Treatment with trastuzumab increases HF risk within 1–2 years of treatment and anthracycline‐based chemotherapy increases HF risk in the first 10 years after treatment. Both anthracyclines and trastuzumab cure many women of their cancers, and the absolute gain for a typical woman selected to receive chemotherapy is usually >5% reduction in BC mortality risk over the next 10 years. For most women this is likely to substantially exceed treatment‐related HF risk. However, our results do emphasize the need to support ongoing efforts to evaluate preventative strategies.This work was supported by the Dutch Cancer Society (grant number NKI 2008‐3994) and Pink Ribbon (grant number 2012.WO39.C143) FD, CT, and SD received funding from Cancer Research UK (grant number C8225/A21133), the British Heart Foundation Centre for Research Excellence, Oxford (grant number RE/13/1/30181) as well as core funding from Cancer Research UK, the UK Medical Research Council and the British Heart Foundation to the Oxford University Clinical trial Service Unit (grant number MC_U137686858).Conflict of interest: G.S.S.: institutional research support from Roche; modest. All other authors have nothing to disclose.Methods S1. Details of the data collection procedures and the eligibility criteria for the cohort.Methods S2. Grading according to adaptation of the National Cancer Institute Common Terminology Criteria for Adverse Events versions 3.0 and 4.0.Methods S3. Radiation dosimetry.Table S1. Radiotherapy techniques received by 408 women with breast cancer at the Netherlands Cancer Institute or the Erasmus MC Cancer Institute in the Netherlands during 1970 to 2009.Table S2. Reasons for exclusion of cases.Table S3. Characteristics of cases and controls by chemotherapy and trastuzumab treatmentTable S4. Characteristics of included casesTable S5. Breast cancer characteristics of heart failure (HF) cases and matched controlsTable S6. Additional analyses on associations between breast cancer treatment and heart failure (HF) risk with restrictions on (I) cases with unknown recovery status 1 year after diagnosis of HF, (II) cases treated with trastuzumab, and (III) patients with a second malignancyTable S7. Time between breast cancer diagnosis and heart failure (HF) diagnosis by type of chemotherapy and trastuzumab treatmentTable S8. Associations between estimated mean left ventricular dose and heart failure (HF) riskTable S9. Associations between patient‐related risk factors at breast cancer diagnosis and heart failure riskClick here for additional data file.


Violent behavior, police brutality, and racial discrimination are currently at the forefront of society’s attention, and they should be. We investigated whether mild sleep loss—as typical for many adults throughout the work week—could aggravate the socio-emotional-cognitive processes contributing to violence and discrimination. In a sample of 40 healthy young adults, we either experimentally restricted participants’ sleep for four nights (6.2 h/night) or let participants obtain normal sleep (7.7 h/night)—and then had them complete the Police Officer’s Dilemma Task. In this computerized task, the participant must rapidly decide to shoot or not shoot at White and Black men who either are or are not holding a gun. Results showed significant racial biases, including more and quicker shooting of Black targets compared to White targets. Furthermore, signal detection analyses demonstrated that mild sleep restriction changed participants’ decision criterion, increasing the tendency to shoot, even when controlling for psychomotor vigilance, fluid intelligence, and self-reported desirability to behave in a socially acceptable manner. The increased tendency to shoot was also observed in participants who reported believing that they had adapted to the sleep loss. Future experimental research using trained police officers will help establish the generalizability of these laboratory effects. Importantly, sleep loss is modifiable via organization-level changes  and individual-level interventions , suggesting that if sleep loss is corrected, it could save lives—including Black lives. At the trial, it was revealed that the police officer was “fatigued” from having worked 40 h in the previous four days, including just finishing a shift that lasted at least 13 h2. While there are many racial bias-related components of the Guyger/Jean case and other police shootings that warrant empirical investigation, the observation that Guyger was “fatigued” at the time of the shooting should be of particular interest to sleep researchers.On the night of September 6, 2018, a White police officer returned to what she believed was her apartment, opening the door to find Mr. Botham Jean, a Black man. The officer, Amber Guyger, quickly pulled her gun and shot him in the chest, killing him. Botham Jean was unarmed and simply eating ice cream in his own—not the officer’s—apartment3, with some estimating that sleep in United States citizens has dropped from nearly 8 h/night in the 1940s to 7 or fewer hours/night more recently4. Sleep loss is common among people of many different professions, but because police officers carry firearms and often must handle potentially hostile situations, it is crucial to recognize that their shifts can be particularly long, variable, and circadian-misaligned5. In a large, representative sample, 40% of police officers had clinical-level sleep disorders and more than ¼ of officers reported falling asleep while driving at least once per month6. Such widespread sleep loss—whether in police officers or any other citizen—is likely to be consequential. After all, acute and chronic sleep loss are known to have numerous neurobiological consequences for nearly all people .Chronic sleep loss has been called an “epidemic”8. Discrimination is, of course, driven by prejudice and racism, but there are at least three additional mechanisms by which sleep deprivation could contribute to when and how discrimination manifests. First, sleep deprivation can alter frontoparietal attentional network functioning10. For decades, researchers have known that sleep restriction slows responding and increases lapses of attention12. Relatedly, if one’s attentional resources are depleted, then they may lack the ability to inhibit prejudices they hold that are typically suppressed13. Second, sleep deprivation can increase emotional reactivity. In one experiment, participants either slept normally or were sleep deprived and then shown negative images . Sleep deprivation increased amygdala reactivity to the negative images due to decreased connectivity between the medial prefrontal cortex and the amygdala14. Third, sleep deprivation can alter threat perceptions. In a recent study, participants who either were sleep deprived or had normal sleep were shown a series of faces and asked to classify them as threatening or non-threatening15. Following sleep deprivation, more faces were rated as threatening, a pattern that corresponded to activity in the salience detection network8. Whether sleep deprivation’s effects on attention, emotional reactivity, or threat perception translate to greater discrimination following sleep loss has received minimal empirical study and remains poorly understood21.In the current work, we investigated sleep loss as a potent mechanism for altering socio-emotional-cognitive processes, which could then correspond to increased expressions of biases and discrimination22. Waketime was set to 7:30 am each day. By using sealed envelopes and blocked randomization, experimenters and analysts remained blinded to participants’ randomly assigned normal versus restricted sleep conditions. The normal sleep condition averaged 1.5 h more sleep per night than the restricted sleep condition, t(38) = 5.87, p < 0.001, d = 1.85 (Table t(38) = 4.02, p < 0.001, d = 1.27], greater moodiness , and poorer sustained attention  = 2.16, p = 0.037, d = 0.68; Table To mirror the chronic mild sleep loss experienced by many individuals during the work week, we randomly assigned 40 healthy adult participants  to maintain a bedtime of either 10:30 pm or 1:30 am from Monday to Friday22 concluded with the Police Officer’s Dilemma Task24. This task was developed to simulate the real-world challenge of police officers needing to make quick decisions in response to perceptually ambiguous situations . Participants were shown scenes that were either empty (no person) or contained a target (person). The target person was either unarmed or armed with a gun and either White or Black, and participants had to quickly decide whether to shoot or not shoot the target. We analyzed accuracy, reaction times, timeouts (failures to respond within the time limit), and signal-detection-theory metrics by conducting a series of 2 × 2 analyses of variance (ANOVAs) that included target race  and sleep condition .The Friday test sessionF = 5.37, p = 0.026, ηp2 = 0.12, and with quicker response times  = 4.13, p = 0.049, ηp2 = 0.10. On unarmed trials, there were no effects for mean response times (ps > 0.10), but there were far more failures to respond within time limits (timeouts) for Black targets than White targets  = 19.63, p < 0.001, ηp2 = 0.34. This result suggests that participants experienced greater difficulty in quickly identifying the Black targets as non-threatening. Similarly, there were significantly fewer “don’t shoot” responses to unarmed Black targets than unarmed White targets  = 11.45, p = 0.002, ηp2 = 0.23. False alarms were rare and showed nonsignificant effects. We conducted follow-up analyses to determine whether any of the significant effects interacted with gender. All gender main effects and interactions were nonsignificant (ps > 0.05), indicating that men and women demonstrated similar levels of racial biases in the Police Officer’s Dilemma Task. The averaged accuracy and averaged response time metrics were not significantly affected or moderated by sleep condition (ps > 0.05).The results revealed significant evidence for racial biases. On armed trials, participants were more likely to “shoot” Black targets than White targets Fig. A, F and the decision criterion (c) for shooting a target. Similar to previous reports24, there were no significant effects on d′ . Importantly, for c, there was a significant main effect of sleep condition such that sleep restriction (M = − 0.155) caused greater leniency in shooting targets relative to normal sleep (M = − 0.025), F = 4.63, p = 0.038, ηp2 = 0.11. Criterion scores were significantly lower than zero after sleep restriction, t(19) = 3.20, p = 0.005, d = 1.47, but did not differ significantly from zero after normal sleep, t(19) = 0.49, p = 0.49, d = 0.22. Figure F = 7.75, p = 0.008, ηp2 = 0.17. Being well-rested led to a more conservative criterion for White targets, t(38) = 3.89, p < 0.001, d = 1.23, but this benefit of rested sleep did not extend to Black targets, t(38) = 0.27, p = 0.79, d = 0.09. In other words, all groups showed a lenient bias except for well-rested participants’ responses to White targets. The interaction remained statistically significant even when controlling for participants’ psychomotor vigilance, fluid intelligence, self-reported desirability to behave in a socially acceptable manner, and self-reported belief that they had adapted to the sleep loss, F = 6.07, p = 0.019, ηp2 = 0.15.An effect of sleep condition emerged when conducting analyses based on signal detection theory. We distinguished sensitivity to armed targets  = 0.74, p = 0.40, ηp2 = 0.02 . Women and men showed identically lenient c scores after sleep restriction  and similar c scores after normal sleep  = 1.84, p = 0.19, ηp2 = 0.09). Interestingly, when limiting the sample to only White participants, the sleep restriction effects on decision criterion were exacerbated. For example, the effect size increased from ηp2 = 0.11 in the overall sample to ηp2 = 0.37 in only the White participants, F = 10.50, p = 0.005. The sleep by race interaction also increased in effect size from ηp2 = 0.17 in the overall sample to ηp2 = 0.39 in the White participants, F = 11.64, p = 0.003.The effects of sleep restriction and target race on decision criterion were not moderated by gender, To promote social justice, society must address violent behavior, police brutality, and racial discrimination. The current data suggest that some of these behaviors may be exacerbated by sleep loss, even when the sleep restriction is relatively mild (6.2 h/night), even when sleep restricted individuals believe they have “adapted” to the short sleep, and even in individuals with inclinations toward behaving in a socially desirable manner.21. In Ma et al.’s21 study, newly recruited officers with self-reported total sleep time − 1 SD below the mean (≤ 5.25 h) showed greater racial bias in the shooter task than officers with self-reported total sleep time + 1 SD above the mean (≥ 8.05 h). Both their study and the current results implicated sleep loss in more “itchy trigger finger” type responding. A distinction in the studies, however, was that Ma et al.21 found that short sleepers were more likely to show a lenient decision criterion toward Black targets, whereas we found sleep restriction affected the decision criterion primarily for White targets. In another recent study25, total sleep deprivation  in college student participants led to more errors on the Police Officer’s Dilemma Task, particularly more “shooting” of unarmed targets . These effects were not mitigated by caffeine consumption. The differences across these data sets and our results could be due to study differences in experimental/correlational design, sample size, sleep measurement, type of sleep loss , sample composition , or other factors that might become evident with further studies.The current experimental findings provide causal support for an earlier correlational study in newly recruited police officers18, perhaps in a circadian-sensitive manner20. Sleep deprivation might lead to increased manifestations of discrimination by altering frontoparietal attentional processes10, amygdala/emotional reactivity processes14, and/or threat perception processes26. The first potential mechanism—altered frontoparietal attentional processes—relates to Ghumman and Barnes’13 idea that resources are needed to maintain control over prejudices, and if such resources are depleted by sleep loss, then biases and discriminatory behaviors will manifest. This idea is logical, but we did not observe direct evidence for it in the current study. When we controlled for performance on psychomotor vigilance and fluid intelligence tasks, we continued to observe that sleep restriction affected the decision criterion to shoot.Our findings also join a growing literature that implicates short and poor-quality sleep in stereotyping and bias toward out-groups32, accounts which are not necessarily mutually exclusive with the altered threat perception account.Distinguishing the amygdala/emotional reactivity and threat perception accounts is trickier because these views predict fairly similar outcomes. For example, sleep loss may make one react more emotionally to negative stimuli, manifesting in this paradigm as “shoot” responses on armed target trials. However, if threat perception is elevated after sleep loss, then “shoot” responses should increase across both armed and unarmed target trials. The collective data on decision criterion, therefore, favored the altered threat perception account. Nonetheless, we cannot dismiss the possibility that sleep loss also affects the decision criterion to shoot via amygdala/emotional reactivity, inhibitory inefficiency, impulsivity, altered ethical decision making, or general tendencies toward aggressionHealth disparities refer to group differences in disease rates/outcomes that are systematic, avoidable, and unfair33. For example, the Centers for Disease Control and Prevention34 report that Black or African American individuals have considerably higher rates of diabetes, hypertension, heart disease, and HIV infection than White and Asian American individuals 36.The purpose of the current study was to investigate the causal effects of sleep loss on socio-emotional-cognitive processes that could contribute to racial discrimination. Another emerging literature that connects sleep and racial discrimination falls under the umbrella of health disparities. upstream determinants influencing downstream determinants. Upstream determinants refer to fundamental social/environmental causes, including differences in socioeconomic status, discrimination, and other societal inequities. Downstream determinants refer to the individual’s experiences and can include allostatic load, self-determination, and health behaviors 38. Pertinent to the present work, racial/ethnic differences in sleep health are recognized as markers of health disparities 47. Furthermore, sleep disparities are emerging as an important contributor to race/ethnic disparities in cardiovascular52, metabolic53, and cognitive55 health outcomes. Clearly, sleep health is important in all communities, even when isolated from matters of violence and aggressive race-based discrimination.One of the leading models for explaining health disparities points to 56). On the other hand, the limited variability in participant demographics hindered us from examining whether effects were driven by in-group/out-group determinants58 versus general stereotyping of Black men59. Increasing diversity in participant enrollment is a longstanding problem in both psychological and medical research62. Overcoming barriers to participant representation requires additional time and monetary resources for recruitment, collaboration with community leaders, and cultural tailoring63. It also requires increasing representation at the level of scientists, editors, and funding agencies65. In other words, academia as a whole must acknowledge and work to address its own systematic biases.One of the limitations of the current study was the sample size, including a limited number of participants from non-White groups. On the one hand, this limitation does not undermine the primary purpose of understanding how majority groups (White participants) display racial biases and altered behaviors under mild sleep restriction  shielding was not observed in a correlational study on sleep and shooter bias in newly recruited police officers21; (2) night shift patrol officers were less likely to prevent deadly outcomes in video-based use-of-force simulators than day shift patrol officers66; (3) police officers sleep even worse than the general public6; and (4) workers in other fields that require extensive, safety-focused training  still show susceptibility to sleep loss and shift-work fatigue70. Therefore, sleep loss deserves closer consideration by public officials and law enforcement as an insidious culprit underlying people’s sometimes faulty judgments and impulsive behaviors.Police work is one of the most sleep-depriving professions72. Workplace sleep education programs73, behavioral change programs74, targeted memory reactivation interventions75, culturally tailored and personalized programs78, and schedules allowing for circadian alignment79 have all been shown to be effective. Based on the current results, as well as the literature on health disparities, it appears that correcting sleep loss in society may play a significant role in saving lives, including Black lives.To eliminate discriminatory behaviors in society—including the shooting of unarmed Black individuals—there will be no substitute for eliminating underlying racism within individuals and systems. To achieve this end, education, policy changes, and individual efforts will be key. But, we also contend that there is room for reducing sleep debt in society80. They received monetary compensation for participating. Advertisements referred to the study as examining Sleep and Social Cognition to prevent expectation effects that would have emerged if the study were advertised as testing racial biases. Exclusion criteria included being under age 18 or over the age of 30, being a habitual short sleeper (< 7 h per night), and having clinically-diagnosed sleep disorders. Two participants did not complete all study sessions. Because there were only four African American participants we were unable to examine in-group versus out-group effects in this study; therefore, we excluded those data from the Police Officer’s Dilemma Task analyses (their data were included in other measures collected as part of this larger sleep study22). The study was approved by the Baylor University Institutional Review Board and all research was performed in accordance with relevant guidelines/regulations. All participants signed informed consents prior to the study and were debriefed upon study completion.Forty-six adult participants were recruited through flyers and social media advertisements in spring 2018. The sample size was determined a priori to detect a large condition effect size, as often observed in sleep restriction studies80). Across the week, we measured sleep using wristband actigraphy, which is designed to detect ambient light and movement (accelerometer-based).The 5-day study consisted of two 1.5 h in-lab experimental sessions – one on Monday and one on Friday. For the four nights between each session, participants were instructed to maintain a wake time of 7:30 am and were randomly assigned to maintain a bedtime of either 10:30 pm  or 1:30 am (restricted sleep condition). To promote ecological validity, participants slept in their home environment , which has been validated for distinguishing sleep/wake state against the gold standard of polysomnography84), daytime sleepiness , social desirability86, and mood disturbances (Profile of Mood States87). Participants additionally completed three cognitive tests: the psychomotor vigilance test12, reading span88, and Raven’s Advanced Progressive Matrices89. At the end of Session 1, participants received the actigraphy device and sleep diary, and they were randomly assigned to the normal sleep and restricted sleep conditions. Assignment order was determined using the blocked random assignment method  using the sealedenvelope.com online tool. To minimize the risk of experimenter bias, the researchers who interacted with the participants were masked to each participant’s experimental condition. We accomplished masking by having a research staff member who would not be interacting with participants generate the random assignments and seal participants’ condition assignments in envelopes. Only after participants completed Session 1, did a research staff member hand the participant a sealed envelope with their condition with the instruction to open the envelope after leaving Session 1. Participants were explicitly instructed to not mention their assigned sleep condition to the experimenter as they were leaving or when they returned for Session 2. Participants were instructed not to nap during the week.At Session 1 (Monday), participants completed a series of questionnaires. We measured recent sleep quality  who are either White or Black24. The participant’s objective is to shoot (Q key) the armed targets and to not shoot (P key) the unarmed targets. Armed targets are holding either a revolver or a pistol, whereas unarmed targets are holding an aluminum can, a camera, a cell phone, or a wallet. In the procedure, empty scenes continuously flash in 500–1000 ms intervals, and after 1–4 empty scenes, a target scene will appear. After 16 practice trials, participants completed 100 experimental trials . To simulate the speeded nature of real world dilemmas, participants had to respond within 630 ms, otherwise the trial resulted in a timeout90. Response times were analyzed on correct trials. Accuracy data produced estimates for correct hits (shooting an armed target), misses (not shooting an armed target), false alarms (shooting an unarmed target), and correct rejections (not shooting an unarmed target). Following previous methods24, we subjected these accuracy data to signal detection analyses to produce estimates of d′, which reflects sensitivity, or the ability to discriminate armed from unarmed targets . We also generated estimates of decision criterion, or c, which reflects the threshold one sets for making a shoot response. Positive c values indicate a conservative threshold, such that one favors a don’t-shoot response; negative c values indicate a lenient threshold akin to having an “itchy trigger finger.” Signal detection estimates (d′ and c) were calculated separately for White targets and Black targets.At Session 2 (Friday), participants returned to the laboratory at the same time as on Monday . We asked participants if they believed they had adapted to the sleep loss, and then re-administered the daytime sleepiness scale, mood disturbances scale, cognitive measures, and a medical error vignette taskd′ = zH = ZFA and criterion was calculated as c = − 0.5 X (zFA + zH). For both calculations, zFA refers to the z-score of false alarms and zH refers to the z-score for hits . We conducted a series of 2 × 2 mixed analyses of variance (ANOVA) in which condition  varied between subjects and target race  varied within subjects. Alpha was set to 0.05 and all tests were two-tailed. Effect sizes were estimated using Cohen’s d and partial eta squared.Statistical analyses were completed using SPSS 26 (IBM) and graphically displayed using Prism 8.4 (Graphpad). D prime was calculated as


No significant differences were observed between brains treated with encapsulated hUC‐MSCs compared to appropriate controls. Proteomic data were highly robust and reproducible, indicating the suitability of this approach to map differential protein expression caused by the implants. The lack of differences between conditions suggests that the effects of implantation may be minimal. Alternatively, effects may only have been focal and/or could have been masked by nonrelevant high‐abundant proteins. For follow‐up assessment of local changes, a more accurate dissection technique, such as laser micro dissection, and analysis method are recommended.Parkinson's disease (PD) is the most common neurodegenerative disorder of movement worldwide. To date, only symptomatic treatments are available. Implantation of collagen‐encapsulated human umbilical cord mesenchymal stem cells (hUC‐MSCs) is being developed as a novel therapeutic approach to potentially modify PD progression. However, implanted collagen scaffolds may induce a host tissue response. To gain insight into such response, hUC‐MSCs were encapsulated into collagen hydrogels and implanted into the striatum of hemi‐Parkinsonian male Sprague–Dawley rats. One or 14 days after implantation, the area of interest was dissected using a cryostat. Total protein extracts were subjected to tryptic digestion and subsequent LC–MS/MS analyses for protein expression profiling. Univariate and multivariate analyses were performed to identify differentially expressed protein profiles with subsequent gene ontology and pathway analysis for biological interpretation of the data; 2,219 proteins were identified by MaxQuant at 1% false discovery rate. A high correlation of label‐free quantification (LFQ) protein values between biological replicates ( For the duration of the experiment, animals were allowed food and water ad libitum.All experiments involving the use of animals were carried out in the National University of Ireland, Galway, in accordance with relevant guidelines and regulations, completed under license by the Irish Department of Health and Children and the Irish Health Products Regulatory Authority, performed in compliance with the European Union Directive 2010/63/EU and S. I No. 543 of 2012, and approved by the Animal Care and Research Ethics Committee at the National University of Ireland, Galway. Male Sprague–Dawley rats, weighing 200–225 g on arrival, were obtained from Charles River, UK. Animals  at 37 °C with minimum essential medium alpha  containing 10% of fetal bovine serum (Sigma), 1% penicillin streptomycin (Biosciences), and 1 ng/ml of human fibroblast growth factor (hFGF). Media were changed every other day. At passage number 3, cells were harvested to proceed with collagen encapsulation. Cells were encapsulated at either 10,000 or 2,500 hUC‐MSCs/μl into 3 μl of collagen hydrogel as described above. After 5 days, collagen hydrogels were degraded for 30 min at 37 °C with collagenases from Clostridium histolyticum . Cell viability was assessed by using the trypan blue exclusion test.hUC‐MSCs were purchased at Orbsen Therapeutics at passage number 2. hUC‐MSCs were cultured in a 6‐well plate under hypoxic conditions (2% O2.42 for induction and 2% in O2 for maintenance) in a stereotaxic frame with the nose bar set at −4.5 mm  or −2.3 mm . To induce Parkinsonism, rats received a unilateral MFB lesion using 6‐OHDA  at stereotaxic coordinates anterior–posterior (AP) −4.0 mm, medial–lateral (ML) −1.3 mm (from bregma), and dorsal–ventral (DV) −7.0 mm below dura. For transplant surgery, rats received unilateral intrastriatal transplants in a volume of 3 μl of hUC‐MSCs alone , collagen alone (n = 10), collagen‐encapsulated hUC‐MSCs  or saline solution (n = 10) at stereotaxic coordinates AP 0.0, ML −3.7 mm (from bregma), and DV −5.0 mm below dura  or 14 days (n = 20) after implantation by terminal anesthesia and were transcardially transfused with 100‐ml heparinized saline solution. Brains were rapidly removed, snap frozen in liquid nitrogen, and stored at −80 °C until further analysis.All surgeries were performed under isoflurane anesthesia  and ground in 8‐M urea in 10‐mM Tris pH 8 buffer for protein extraction. Protein concentration was determined with 2D‐Quant kit , and subsequently, 10 μg of total protein (5 μl) was incubated with 2‐μl 10‐mM dithiothreitol for 30 min at room temperature to reduce disulfide bonds. Thereafter, cysteine residues were alkylated with 50‐mM 2‐chloroacetamide in 50‐mM ammonium bicarbonate (ABC) for 20 min at room temperature in the dark. Then 0.5 μg/μl of the endopeptidase LysC was added and incubated for 3 h at room temperature. Samples were then diluted 4× with 50‐mM ABC and incubated overnight at room temperature with 1‐μg trypsin/50‐μg total protein. Bond Elut C18 Omix tips (Agilent) were used to desalt and concentrate the peptide mixtures prior to LC–MS/MS measurements.2.6m/z 150–2,200. Data‐dependent acquisition of MS/MS spectra (AutoMSn) was performed using a 3‐s duty cycle at 2‐Hz acquisition rate for full MS spectra and a variable number of MS/MS experiments. Precursor ions within the range of m/z 400–1,400 with charge state z ≥ 2+ were selected for MS/MS analysis with active exclusion enabled.Measurements of each sample were performed using C18 reversed phase liquid chromatography in combination with online tandem mass spectrometry (LC–MS/MS) in data‐dependent acquisition mode. Two microliters of trypsin digested sample was loaded onto the trapping column  using 0.1% formic acid at 7,000 nl/min for 3 min. Next, peptides were separated on a C18 reversed phase analytical column  at 40 °C using a linear gradient of 5%–35% acetonitrile, 0.1% formic acid in 240 min at 600 nl/min. Measurements were performed using a nanoflow ultra‐high‐pressure liquid chromatograph  coupled online to an orthogonal quadrupole time‐of‐flight mass spectrometer  via an electrospray ionization source . The mass spectrometer was operated in positive ion mode to acquire line spectra in the mass range of For the analysis of detected peptides of 6‐OHDA‐lesioned area versus intact area, a 120‐min gradient was used, instead of 240 min. The rest of the settings were the same as described above.2.7Rattus norvegicus database (SwissProt) with added sequence of the known contaminant Bos Taurus Type I collagen using the built‐in Andromeda search engine. The decoy database used for false discovery rate validation contained the reversed protein sequences. Desired maximum false discovery rate at both peptide and protein identification levels was set to 1%. MaxQuant MS/MS database searches were performed with 10‐ppm and 0.5‐Da mass tolerance for precursor ions and fragments ions, respectively. Carbamidomethylation (at cysteine residues) was specified as fixed modification, whereas deamidation (at asparagine and glutamine residues), acetylation (protein N‐terminus), and oxidation (at methionine residues) were selected as variable modifications. Trypsin was selected as a specific enzyme, and a maximum of two missed tryptic cleavages was accepted.Detected peptides were analyzed using MaxQuant software (v1.6.2.6) and searched against the For the analysis of detected peptides of 6‐OHDA‐lesioned area versus intact area, PEAKS® studio X software was using identical settings as mentioned above for MaxQuant for MS/MS database searches.2.8http://www.pantherdb.org).Gene Ontology (GO) and pathway analysis were performed using PANTHER Classification System  values were performed using metaboanalyst  and the R‐programming platform . An adjusted p value < .05 was considered as statistically significant. The threshold for the fold change (FC) in the volcano plot was set at 2.0.Pearson's correlation between samples, principal component analysis (PCA), one‐way ANOVA with Fisher's least significant difference (LSD) post hoc test, pairwise 33.1A total of 2,219 proteins were identified using shotgun proteomics of dissected striatum samples. For 12 out of 49 samples, we observed poor mass spectrometry signals. Replicate sample preparation and measurements yielded identical results for these 12 samples that were, thus, omitted from this study because of poor sample quality (data not shown). Final number of samples in downstream data analysis can be found in Table ). Detailed analysis of the sample with the lowest correlation coefficient (r = .88), which is still high  of the LFQ values of biological replicates. In all cases, the intra‐group CV was lower than 15% (data not shown), which is consistent with good analytical accuracy and minimal biological variation. Then, we created a matrix of Pearson's correlations of the LFQ values; all the proteins identified in one sample were correlated with all the proteins found in another one. For all comparisons, a correlation higher than .88 was obtained, indicating high robustness and reproducibility of the technique. Moreover, this high correlation factor means there is close similarity between samples, indicating similar protein expression profiles in all samples Figure . Detailh Figure , reveale3.2t‐tests and volcano plots to identify statistically and biologically significant changes  and time‐window after implantation (1 or 14 days). We analyzed large regions of striatum to map the expected dramatic changes in the brain proteome. The PCA plot showed close proximity of the scores for all samples, which shows that the majority of consistent variation in protein expression is not related to group differences that is underlined by the low percentage of variance explained by principal components PC1 (9.2%) and PC2 (6.7%) Figure . One‐wayA GO enrichment analysis could not be performed on host tissue responses as no statistically different proteins were identified between groups. However, we did GO studies and pathway analysis of the whole protein set of identified proteins (data not shown). All identified pathways are related to brain specific processes, as well as metabolic and inflammatory processes, confirming correct protein annotation of our identified proteomes that could have been involved in the expected tissue responses to the implant.3.3The lack of differences between treatment conditions could be explained by a lack of treatment effect or by localization of the effect to a small region with masking of differential proteins by other proteins of the dissected area. To investigate this, we compared the proteomic profiles of the intact striatal area of the brain with the area injured with 6‐OHDA injection. We hypothesized that, if no differences between these two different areas could be detected, it would indicate that the effects were too local and, thus, could not be detected.r > .89; Figure t‐test as well as volcano plot analysis with post hoc testing showed no significant differences between groups . Pearson's correlation between samples showed high correlation between samples  was previously described with positive outcomes: diminished the host brain's response and increased survival and reinnervation of the implanted cells .We used hUC‐MSCs instead of another type of stem cell because hUC‐MSCs are largely available, easy to obtain and to expand, raise fewer ethical concerns, are non‐immunogenic, and release several anti‐inflammatory proteins and key neurotrophic factors. Specifically, hUC‐MSCs secrete large amounts of GDNF, which is specifically beneficial for dopaminergic neurons  there may be no effects strong enough to be detected using shotgun proteomics and (b) the relative large dissected area in comparison with the small area of implantation diluted the effects. This second explanation is corroborated by the finding that also no differences were observed between intact area (no surgery) and lesion area (6‐OHDA injection). Surgical procedures activate the immune response and cause changes in the surrounding area, and 6‐OHDA injection causes the death of dopaminergic neurons. In LC–MS/MS, the detection of low‐abundant proteins is hampered by the presence of high‐abundant proteins  in combination with LC–MS/MS or mass spectrometry imaging (MSI) may be alternatives. Both techniques present advantages but also limitations. LCM has already been used to isolate brain cell populations for gene and protein expression analysis (Fustin, Karakawa, & Okamura, In summary, we intended to determine the proteomic changes in the striatum of the 6‐OHDA PD rat model after implantation of collagen hydrogel‐encapsulated hUC‐MSCs. Our results confirmed the high robustness and reproducibility of our analysis but could not determine differences between groups. We believe that the lack of differences between groups is because, if there is an effect, it is neither strong nor widespread. For future experiments, we suggest that LCM combined with LC–MS/MS or MALDI imaging techniques, despite their own disadvantages, may yield a more detailed insight into the host tissue proteomic response to the transplanted encapsulated cells in order to be able to assess the efficacy and safety of collagen‐encapsulated hUC‐MSCs as a disease modifying therapy for PD.The authors have declared that there is no conflict of interest.A.S. collected the data, performed the data analysis, and wrote the manuscript. S.C. and V.A. performed the in vivo experiments. P.K. helped with the biostatistical analysis. A.S., H.W., J.G., H.B.K., and M.V. interpreted the data and revised the manuscript. All authors read the manuscript for intellectual content and commented on the final version of the manuscript.


Although it is known that geriatric syndrome is associated with the development of frailty, it is not known whether an amelioration of geriatric syndrome also improves shared risk factors and frailty.In total, 67 community‐dwelling older people  participated in this study (41 were classified as pre‐frail and 26 as frail). We analyzed indices of physical frailty and cognitive depression, exercise tolerance and health‐related quality of life as frailty related indices, and the participants completed a questionnaire regarding common geriatric symptoms  using numeric ratings. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study (J‐CHS) criteria. The participants then underwent a far‐infrared low‐temperature sauna (FILTS) program twice a week for 3 months and the above parameters were reassessed.P = 0.013) and the cumulative numeric rating for geriatric syndromes  were independent determinants of the change in the J‐CHS score.After the FILTS program, there were significant differences in usual walking speed, peak oxygen uptake, Geriatric Depression Scale‐15, health‐related quality of life and the severity of several geriatric symptoms. Of the 67 participants, 18 showed improvements in their J‐CHS frailty score, 47 showed no change and two showed reductions. Linear regression analysis showed that the change in the numeric rating of the coldness of extremities (B = −0.105, Geriatr Gerontol Int 2020; 20: 892–898.A 3‐month FILTS program ameliorates geriatric syndrome, the severity of frailty and frailty related indices in older Japanese people.  Frailty is a common clinical syndrome in older adults that carries a higher risk of poor health outcomes, including falls, disability, hospitalization and mortality.Common geriatric conditions include delirium, falls, frailty, dizziness, syncope and urinary incontinence,We hypothesized that far‐infrared low‐temperature saunas (FILTS) might be able to reduce the degree of frailty in the elderly population, thereby interrupting feedback mechanisms and ameliorating shared risk factors and the geriatric syndrome.A previous study has shown that FILTS ameliorates: dyspnea associated with chronic heart failure  and chronic obstructive pulmonary disease; exercise intolerance associated with chronic heart failure; pain associated with fibromyalgia, chronic fatigue syndrome; ulcers and other skin lesions associated with peripheral artery disease; constipation associated with ileus; mild depression; and anorexia associated with depression.Therefore, in the present study, we aimed to determine whether FILTS ameliorates features of the geriatric syndrome, and whether such improvement is associated with the amelioration of frailty and frailty related indices.Sixty‐seven community‐dwelling older people (18 men and 49 women) living in the Tokyo metropolitan area participated in this study. Their mean age was 79.6 ± 6.5 years (range 66–93 years). None of the participants were hospitalized at the time, but all were being treated on an outpatient basis at the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology. The inclusion criteria were as follows: pre‐frailty or frailty, determined using the Japanese version of the Cardiovascular Health Study (J‐CHS) criteriaThe clinical characteristics of the participants are summarized in Table Frailty and pre‐frailty were diagnosed using the Japanese version of the Cardiovascular Health Study (J‐CHS) criteria.We created a questionnaire that aimed to grade the symptoms of geriatric syndrome. The symptoms that were assessed using this questionnaire were coldness of extremities, leg edema, breathlessness, urinary incontinence, chronic headache, chronic pain , a sense of numbness, anorexia, constipation, insomnia and skin trouble, all of which are features of geriatric syndrome in outpatients. The questionnaire was used to record the presence or absence of each symptom, and to grade the severity of each using a numeric rating scale from 0 to 10, where 10 is very severe. The major symptoms of geriatric syndrome, falls and aspiration, were excluded from this questionnaire because these can be recorded as present or absent, but it is difficult to grade their severity using a numeric scale.The FILTS program used a far‐infrared dry sauna  that was maintained at 60°C. Participants remained seated for 15 min, and then rested in a supine position, while covered with a warm blanket, for an additional 30 min. All the participants were weighed before and after each FILTS session and instructed to drink more water than their weight loss from perspiration. The FILTS program consisted of two sessions per week for 3 months, for a total of 24 sessions.Body composition was assessed using skeletal muscle mass index and body mass index. Physical performance was assessed using handgrip strength, timed up‐and‐go test and usual walking speed (UWS). Cognitive function and depressive symptoms were assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA‐J)R2 deviation from zero; a priori: compute the required sample size – given α, power and effect size) using sample size software .A sample size of 54 participants was calculated for 80% power, α = 0.05, β = 0.2, and anticipated effect size = 0.35  between pre‐frail and frail older people Table . To compThis study was approved by the ethics committee of the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology (authorization number: 240301) and conformed with the principles outlined in the Declaration of Helsinki. All participants gave their written informed consent before data collection.In total, 67 participants successfully completed the 3‐month FILTS program and no adverse events related to the program were recorded; 41 (61.2%) participants were classified as pre‐frail and 26 (38.8%) as frail. The pre‐frail and frail participants were of similar ages (78.9 ± 6.3 vs. 80.5 ± 6.7 years). The clinical characteristics of each group are summarized in Table Table 2/weight (mL/kg/min), peak power (W), GDS‐15 score and PCS in SF‐8; none of the indices worsened during the program. Among the components of SF‐8, significant improvements occurred in physical function , general health  and emotional score . There were no significant changes in physical score , physical pain , vitality , social functioning  or mental health .Table P < 0.05).Table We compared each index of frailty  before and after the FILTS program using the chi‐squared test Table , and fouP = 0.013) and the cumulative numeric rating of geriatric syndrome  were independent determinants of the change in J‐CHS score .Table Our study used data from consecutively recruited pre‐frail and frail older outpatients. Patients had no one specific underlying condition and were regularly attending the Tokyo Metropolitan Geriatric Hospital as outpatients for the management of chronic diseases. The prevalences of pre‐frailty and frailty were 61.2% and 38.8%, respectively. A previous study reported the prevalences of robustness, pre‐frailty and frailty to be 30.3%, 59.8% and 9.9% in Japanese men, and 25.3%, 64.7% and 10.0% in Japanese women, respectively.In total, 67 participants successfully completed the 3‐month FILTS program and experienced no adverse events, which demonstrates the safety of FILTS for community‐dwelling pre‐frail and frail outpatients with chronic disease Table . Table 22/weight 14.3 ± 4.5 mL/kg/min and peak metabolic equivalent (METs) 4.1 ± 1.4 METs). Previously, we have reported that the peak VO2/weight and peak METs in robust, pre‐frail and frail individuals are 18.7 ± 4.0 mL/kg/min and 5.6 ± 1.0 METs, 16.7 ± 4.5 mL/kg/min and 5.2 ± 1.0 METs, and 14.7 ± 4.1 mL/kg/min and 4.4 ± 0.9 METs, respectively2/weight ≤14 mL/kg/min is a hallmark of low physical fitness, and it is accepted as an indication for cardiac transplantation in patients with heart failure with severe left ventricular dysfunction.Table 2/weight, peak power, GDS and SF‐8 PCS. It ameliorated weight loss and low physical activity but not slowness , weakness or exhaustion , peak VO2/weight , peak power  among female, but not in male .In addition, we analyze gender‐specific analyses among UWS, peak VOTable We next used multiple linear regression analysis to determine whether the J‐CHS score improved because of the changes in numeric ratings for each of the symptoms, and found that the cumulative numeric rating for geriatric syndrome improved during the FILTS program. Table et al. first described the accumulation of deficits in older people in the Frailty Index, which incorporates the following in one index: symptoms; signs; diseases; disabilities; laboratory, radiographic and electrocardiographic abnormalities; and social characteristics.Mitnitski To date, changes in exercise and nutrition have been used to prevent or ameliorate frailty in older adults.The present study had several limitations. First, although we recruited clinical outpatients consecutively and non‐selectively, there may have been some bias. This could be because we excluded potential participants with acute or unstable diseases and those who regularly exercised. Second, our sample size was relatively small to describe the data of each gender, and third, there was no control group.In conclusion, amelioration of the geriatric syndrome, with a 3‐month FILTS program, is associated with an improvement in frailty score and frailty related indices in a group of elderly Japanese people.The authors declare no conflict of interest.MS, TT, MN and KH made substantial contributions to the study design. MS, TT and MN contributed to the acquisition of data and performed the statistical analyses. KH, HF, SK and HI contributed to interpreting the data. MS, KH, TT and MN wrote the manuscript drafts. All the authors critically reviewed and contributed significantly to the intellectual content of the manuscript. All the authors agreed on the final content of the manuscript.Table S1 Comparisons of the indices of frailty  before and after the intervention using the chi‐squared test.Click here for additional data file.


Spinocerebellar ataxia type 1 (SCA‐ATXN1) is an inherited progressive ataxia disorder characterized by an adult‐onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described.To describe a retinal phenotype and its functional relevance in SCA‐ATXN1.We applied optical coherence tomography (OCT) in 20 index cases with SCA‐ATXN1 and 22 healthy controls (HCs), investigating qualitative changes and quantifying the peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIP) volume as markers of optic atrophy and outer retinal layers as markers of maculopathy. Visual function was assessed by high‐ (HC‐VA) and low‐contrast visual acuity (LC‐VA) and the Hardy‐Rand‐Rittler pseudoisochromatic test for color vision.P < 0.001) and GCIP (P = 0.002) were reduced in patients  compared with HCs . Outer macular layers were similar between groups, but reduced in patients with maculopathies. HC‐VA (P = 0.002) and LC‐VA (P < 0.001) were reduced in patients  compared with HCs . Color vision was abnormal in 2 patients with maculopathies.Five patients (25%) showed distinct maculopathies in the ellipsoid zone (EZ). Furthermore, pRNFL (A distinct maculopathy, termed EZ disruption, as well as optic atrophy add to the known nonataxia features in SCA‐ATXN1. Whereas optic atrophy may be understood as part of a widespread neurodegeneration, EZ disruption may be explained by effects of ataxin‐1 gene or protein on photoreceptors. Our findings extend the spectrum of nonataxia signs in SCA‐ATXN1 with potential relevance for diagnosis and monitoring. Spinocerebellar ataxia type one  is a dominantly inherited autosomal progressive ataxia disorder caused by translated CAG‐repeat expansions in the ataxin 1 gene (ATXN1).Against this background, we aimed to investigate neurodegeneration of retina and optic nerve, macular anomalies, and their functional relevance in a cross‐sectional cohort of 20 index cases with SCA‐ATXN1.Twenty patients with genetically confirmed and manifest SCA1‐ATXN1 were prospectively recruited between June 2010 and November 2016 for this cross‐sectional observational study from one university ataxia clinic  and examined at the NeuroCure Clinical Research Center (NCRC). The inclusion criterion was genetically confirmed diagnosis of SCA1‐ATXN1. Exclusion criteria for this analysis included missing retinal optical coherence tomography (OCT) data. Two patients and three eyes in 2 other patients had OCT of insufficient image quality and were excluded from the statistical (but not from the descriptive) analysis. Nine patients (45%) were previously published in a smaller cohort study by Stricker et al., which reported OCT findings from an earlier time point.2 < 0.001; P > 0.999) and age . Best‐corrected high‐contrast monocular visual acuity (HC‐VA) and 2.5% low‐contrast visual acuity (LC‐VA), using retroilluminated Early Treatment in Diabetes Retinopathy Study (ETDRS) at 4 m distance and Sloan charts at 2 m distance, respectively,  as well as monocular color vision assessments applying the Hardy‐Rand‐Rittler pseudoisochromatic test (HRR) were acquired in 12 patients and 5 HCs. The study was approved by the local ethics committee of Charité–Universitätsmedizin Berlin (EA1/17515) and conducted in accordance with the applicable German laws and the current version of the Declaration of Helsinki. All participants gave written informed consent. All data is reported according to STROBE reporting guidelines.For comparison, we included cross‐sectional data of 22 healthy controls (HCs) from the NCRC's normative OCT database matched for sex  with automatic real‐time (ART) function for image averaging was used in all participants.2 and Wilcoxon rank‐sum tests, respectively. Group differences for OCT parameters and visual acuity assessments as well as correlations with clinical metrics were analyzed by generalized estimating equation models to account for within‐patient intereye associations of monocular measurements. All tests and graphical representations were performed with R software .P < 0.05. Because of the exploratory character of our analyses, we refrained from corrections for multiple comparison.Group differences in age and sex between SCA‐ATXN1 and HCs were tested by χData not provided in the article will be shared at the request of other investigators for purposes of replicating procedures and results.We found pathological disruption of EZ in 5 patients , but not pRNFL . Furthermore, disease severity measured by SARA score was correlated neither with pRNFL  nor with GCIP . Number of CAG repeats  were not correlated with pRNFL nor GCIP.In SCA‐ATXN1 patients, time since onset showed a positive correlation with GCIP  consistent with optic atrophy, which are pointing toward a neurodegenerative process in the optic nerve. Together with the reported visual function impairment, these structural changes should be considered as further nonataxia signs in SCA‐ATXN1.The macular pathologies reported here are in line with three previously published cases.atxn1 on photoreceptors. Pathophysiological evidence for this was contributed by Fernandez‐Funez et al., who induced the expression of polyQ‐expanded ATXN1 in retinae of drosophila, which subsequently developed a progressive elimination of retinal cell bodies and axonal projections.It is possible that the macular pathology is caused by a yet unrecognized pleiotropic effect of mutant Next to this first systematic description of the novel ellipsoid zone disruption maculopathy, our results solidify previous reports on optic nerve atrophy as part of the clinical picture of SCA‐ATXN1 showing pRNFL and GCIP, but not mRNFL, thinning. Of note, mRNFL is very thin and has a high intertest variability, making a significant group difference in a small sample unlikely.The reported changes resulted in impaired visual function in our study—with visual acuity decline as well as with color vision deficits in patients with EZ disruption. The magnitude of changes suggest that they are clinically meaningful, and at least the color vision deficits could probably be detected in clinical visual assessments using standard procedures such as Ishihara charts.Given the rarity of SCA‐ATXN1, an important strength of the study is the comparably large sample size. However, the statistical power might have still been insufficient to confirm numerical differences in outer layers where low measurements in eyes with EZ disruption suggest a potential degenerative relevance. Further important limitations of our study include the incomplete clinical and functional  data and the lack of blue autofluorescence and longitudinal data to conclusively confirm a progressive retinal neurodegeneration in SCA‐ATXN1. Especially, investigations in nonmanifest carriers would be of high interest in this respect.Our findings extend the previously established spectrum of nonataxia signs in SCA‐ATXN1 with potential relevance for diagnosis and monitoring. Within the scope of the proposed diagnostic algorithm by Rossi et al.,(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.F.C.O.: 1B, 1C, 2A, 2B, 3AH.G.Z.: 1B, 1C, 2C, 3BM.R.: 1C, 3BC.B.: 1C, 3BS.M.: 1B, 1C, 2C, 3BJ.K.: 1C, 3BA.S.G.: 1C, 3BA.B.: 2C, 3BT.S.‐H.: 1C, 2C, 3BF.P.: 1C, 2C, 3BO.Z.: 1C, 2C, 3BA.U.B.: 1A, 1B, 2C, 3CThe study was approved by the local ethics committee of Charité–Universitätsmedizin Berlin (EA1/17515). All participants gave written informed consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.F.C.O. was employed by Nocturne, unrelated to this manuscript. HGZ reports research grants from Novartis unrelated to this study. J.K. received conference registration fees from Biogen and financial research support from Krankheitsbezogenes Kompetenznetzwerk Multiple Sklerose (KKNMS), not related to this work. An.B. has received CCT devices for research from Konan Medical. F.P. reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, and MedImmune and is a member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. T.S.H. received travel grants from Celgene and speaker honoraria from Roelke pharma and Biogen unrelated to this work. A.U.B. is founder and holds shares of Motognosis and Nocturne. He is named as inventor on several patent applications describing serum biomarkers for MS, perceptive visual computing for tracking of motor dysfunction, and OCT image analysis.T.S.H. received a travel grant from Celgene and speaker honoraria from Biogen and Bayer within the last 12 months.


The incidence of conversion to open cholecystectomy was similar in the three groups (p = 0.37), and we found no significant difference regarding postoperative complications (p = 0.987). Group I had shorter total hospital stays and medical costs  vs Group II and Group III. Early LC within 1 week after PTGBD is safe and effective, with comparable intraoperative outcomes, postoperative complications, and conversion rates to open cholecystectomy. Furthermore, early LC could decrease postoperative length of hospital stay and medical costs.There is no consensus on the optimal timing of laparoscopic cholecystectomy (LC) after percutaneous transhepatic gallbladder drainage (PTGBD) for patients with acute cholecystitis (AC). We retrospectively evaluated patients who underwent LC after PTGBD between 1 February 2016 and 1 February 2020. We divided patients into three groups according to the interval time between PTGBD and LC as follows: Group I (within 1 week), , and Group III (> 1 month) and analyzed patients’ perioperative outcomes. We enrolled 100 patients in this study . We found no significant difference between the groups regarding patients’ baseline characteristics and no significant difference regarding operation time and estimated blood loss ( For patients with AC, LC is recommended soon after onset if there are no contradictions for the procedure. However, the treatment benefit depends on the AC severity and whether the patient can tolerate emergency surgery. Percutaneous transhepatic gallbladder drainage (PTGBD) was first reported in the early 1980s and was recommended in several guidelines to manage patients with AC with a high risk for LC5. PTGBD is beneficial for improving patients’ conditions to permit delayed LC6; however, the optimal time for LC after PTGBD is controversial, and few studies have provided quality evidence. Several papers have discussed the interval time between LC and PTGBD; however, these studies revealed mixed results regarding perioperative outcomes9. Sakamoto et al. performed a nationwide database study; however, OC was included in this study7. The Tokyo guidelines updated in 2018 revealed that there was no consensus regarding the optimal timing of LC after PTGBD1, and, related to various factors, it is still very difficult to perform randomized controlled studies. In the current study, we retrospectively investigated the optimal timing of LC after PTGBD.Laparoscopic cholecystectomy (LC) has now replaced open cholecystectomy (OC) as the first choice for cholecystectomy, with the advantages of less pain, shorter hospital stay, and shorter recovery time. However, debate continues regarding whether LC is beneficial for acute cholecystitis (AC)We divided the 100 patients into three groups: 22 patients in Group I (14 men and 8 women); 30 patients in Group II (16 men and 14 women); and 48 patients in Group III (26 men and 22 women). The mean age of the patients was 65.41 ± 15.43 years (Group I), 68.81 ± 17.36 years (Group II), and 66.71 ± 12.69 years (Group III). Patients’ baseline characteristics appear in Table Group II had higher rates of recurrences cholecystitis  Table . Group Ip = 0.699) and estimated blood loss (p = 0.263) (Table p = 0.373) (Table We found no significant differences between the three groups for operation time ( p = 0.26 Table 3p = 0.699p = 0.987) (Table p = 0.005) and between Group I and Group III (p < 0.001). Postoperative hospital stay was similar between the groups (p = 0.744)  Table . The pats p = 0.74 . Gallbladder contents were aspirated in patients with gallbladder distension. Calot’s triangle was dissected first, and we attempted retrograde gallbladder dissection starting at the fundus in patients with severe inflammation and anatomical difficulty dissecting the pericystic space. The gallbladder was extracted through the subumbilical incision. Conversion to OC was performed, if necessary, as described previously. A right subcostal is made. It is important to obtain good visualization of the gallbladder, Triangle of Calot, and bile ducts. After clarifying the cystic duct, common hepatic duct, and common bile duct, the cystic duct and cystic artery are disconnected. The gallbladder then can be removed from the gallbladder bed of the liver using either electrocautery.The outcome measures constituted outcomes during the interval time, intraoperative outcomes, and postoperative outcomes. Outcomes during the interval time were recurrent cholecystitis and catheter-related complications. Intraoperative outcomes were operation time, estimated blood loss, and conversion to OC, and postoperative outcomes were postoperative complications, total length of hospital stay, postoperative hospital stay, and medical costs. We scheduled telephone interviews or outpatient visits following PTGBD and LC.The data were analyzed using SPSS ver. 17.0 . Descriptive statistics were calculated for demographic and clinical variables and were reported as means ± standard error mean (SEM). Comparisons between groups for categorical variables were assessed using the chi-square test. The Student t test was used to compare two groups for normally distributed quantitative variables otherwise Mann–Whitney test was used. Bonferroni test was used as a post hoc test for intergroup analysis. P < 0.05 was considered statistically significant. All authors had access to the study data and reviewed and approved the final article.The Affiliated Dongyang Hospital of Wenzhou Medical University Institutional Review Board approved the protocol (No. 2020-YX-038) and all participants were provided written informed consent.


Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio‐metabolic disease. We assessed relationships between ART drug class and weight change among treatment‐naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA‐ACCORD).+ cell count. Due to shorter follow‐up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.Adult, treatment‐naïve PWH in NA‐ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non‐nucleoside reverse‐transcriptase inhibitor (NNRTI)‐based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV‐1 RNA level and CD4+ cell counts, and those initiating INSTI‐based regimens had higher odds of >10% body weight increase at two years .Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI‐, 31% started PI‐ and 20% started INSTI‐based regimens , 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI‐based regimens had mean estimated five‐year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two‐year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4PWH initiating INSTI‐based regimens gained, on average, more weight compared to NNRTI‐based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration. Iex (BMI) . Howeverex (BMI) . Among Pex (BMI) , 7, 8, 92) compared to those receiving NNRTI‐ or PI‐based regimens [Integrase strand transfer inhibitors , elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC)) are a more recently available class of antiretroviral medications with a good tolerability profile and, for DTG and BIC, a substantial genetic barrier to the emergence of HIV drug resistance , 11. INSregimens . In otheregimens , 16, 17,regimens , 19.ART‐associated weight gain among PWH may contribute to an increased risk of cardiometabolic disease, but the magnitude of weight gain associated with use of different initial ART regimens has varied in recent studies , 20. Giv2NA‐ACCORD, one of the regional cohorts supported by the International epidemiologic Databases to Evaluate AIDS (IeDEA) consortium sponsored by the National Institutes of Health, is a multi‐site collaboration involving 26 cohort studies representing over 200 clinical and research facilities in the United States and Canada . PWH areFor this analysis, we utilized NA‐ACCORD data on ART‐naive adults who initiated a first regimen that contained an NNRTI, PI or INSTI in combination with dual nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) between 1 January 2007 and 31 December 2016, and had available baseline weight and height information. The date of ART initiation was considered the first occurrence of sustained ART use for more than 45 days. Participants were classified as ART‐naive if there was no recorded ART exposure of more than 45 days prior to the start of a combination NNRTI‐, PI‐ or INSTI‐based regimen  and the viral load at treatment initiation was detectable (≥400 copies/mL). Women who had previously received ART in the antenatal period were considered “naïve” only if their prior ART exposure was for <45 days.The primary aim of this analysis was to assess the relationship between ART class and weight over time among treatment‐naïve participants. Analyses were conducted separately among: (1) the full group of participants who met inclusion criteria, where initial ART was categorized by class as NNRTI‐, PI‐ or INSTI‐based; (2) the sub‐group of participants who initiated an INSTI‐based regimen, categorized as RAL, DTG or EVG; and (3) the sub‐group of participants who initiated either an NNRTI‐ or PI‐based regimen, or RAL, DTG or EVG. For each analysis, NA‐ACCORD sites with fewer than 50 PWH who initiated each ART class/INSTI drug were excluded from the analysis. Additionally, participants on regimens containing more than one major ART class (e.g. NNRTI and INSTI) were also excluded from the analysis.Demographic and clinical characteristics were summarized across the ART/drug categorization using median (interquartile range) or percent with frequency, as appropriate. Kruskal‐Wallis tests assessed the associations of continuous variables with the ART class/drug; Pearson’s chi‐squared tests assessed association between categorical variables and ART class/drug.10‐transformed), cohort site and year of ART initiation. Interactions between ART class/drug and years since ART initiation, sex, race and HIV risk factor were assessed. To relax linearity assumptions, years since ART initiation, age, and baseline weight, CD4 and HIV‐1 RNA were modelled using restricted cubic splines with five knots. Baseline weight and CD4 were the values closest to ART initiation within a window of −180 to +30 days. Baseline HIV‐1 RNA was the value closest to ART initiation within a window of −180 to +7 days. Self‐reported race was dichotomized as white versus non‐white. HIV risk factor was classified as men who have sex with men (MSM), persons who inject drugs , heterosexual and other/unknown. Missing baseline data were multiply imputed using 10 imputation replications. Marginal predicted weights over time along with 95% bootstrapped confidence intervals (CIs) were calculated by ART class/drug and the predicted weights at two and five years after ART initiation were reported.We modelled weight changes over time using multivariate linear mixed effects models treating each participant as a random effect. Participants were censored at the time of a switch to a new ART class (i.e. not including NRTI switches or within‐class switches) or at the first instance of virologic failure. Virologic failure was defined as a plasma HIV‐1 RNA >1000 copies/mL, or at the first of two consecutive detectable HIV‐1 RNA measurements ≥400 copies/mL after previously being virologically suppressed . Models In secondary analyses, to further explore the relationship between weight over time and ART use, we assessed weight gain in excess of 10% at two and five years post‐ART initiation by regimen class, and at two years by individual INSTI medications. Weight at two and five years was defined as the weight closest to those time points and within a window of ±6 months. Persons with missing baseline and follow‐up weight were excluded from these secondary analyses. Using >10% weight gain as an outcome, we used multivariate logistic regression adjusting for the same covariates used in the primary analysis. As in the primary analysis, continuous variables were fit with restricted cubic splines using five knots; however, in this analysis no interaction terms were included. Missing data were multiply imputed with 10 imputation replications.2), overweight (25.0 to 29.9kg/m2) and obese (≥30kg/m2) after three years of ART. Analyses were performed using R .Lastly, we evaluated the proportion of participants who transitioned between the standard BMI categories of normal  nor did we adjust for pregnancy, as these data were not routinely collected in the cohort. Furthermore, only 13% of participants were females; therefore, we might be misrepresenting the population‐level impact of weight gain in the target population of HIV positive individuals initiating ART in the United States and Canada during this period – especially as several studies have shown ART‐associated weight gain to be a greater problem among females , 30. Fin5In this multisite cohort of over 20,000 diverse treatment‐naïve PWH across North America who initiated ART, we found that the use of INSTI‐based ART regimens was associated with higher weight gain up to five years after treatment initiation compared to NNRTI‐based regimens, primarily driven by the use of DTG‐ and RAL‐containing regimens. Additionally, INSTI‐based ART was associated with comparable weight gain to PI‐based regimens. ART‐treated PWH have a high prevalence of obesity and are already at greater risk for metabolic and cardiovascular comorbidities; closely monitoring changes in weight after the initiation of INSTI‐class drugs may identify patients who could benefit from weight loss interventions and closer scrutiny of associated cardio‐metabolic risks.KA serves on an advisory board for TrioHealth. KB receives research funding from Gilead Sciences, and has served as a scientific advisor for Gilead Sciences and Theratechnologies. HC has served on an advisory board for ViiV. JG has served on the National HIV Advisory Boards of Merck, Gilead and Viivhealth. JK receives research funding from Gilead Sciences, and has served as a scientific advisor for Gilead Sciences and Theratechnologies. JLake receives research funding from Gilead Sciences and is a consultant to Gilead Sciences and Merck. MS receives research funding from Gilead Sciences. FP is a consultant and/or on the Speakers’ Bureau for Gilead Sciences, Janssen, ViiV and Merck. JT is a consultant for Gilead Sciences, has served as a scientific advisor to AbbVie, Clearside and Santen, and has grant support from Allergan and NEI. SG, MH, CJ, GK, JLi, VL, JM, RM, WCM, CR, PR, TS, AW and CW report no conflicts of interest.KB, CJ, PR, JLake and JK developed the study design and analysis plan, which was reviewed, modified and approved by RM, KA, FP, JG, CR, SG, MH, JM, JLi, CW, AW, VL, HC, JT, MS, GK and WCM. CJ and PR conducted the statistical analysis with periodic input from JK, JLake, KB and TS. KB, JK, JLake, TS, CJ and PR drafted the initial version of the manuscript, which was then revised by RM, KA, FP, JG, CR, SG, MH, JM, JLi, CW, AW, VL, HC, JT, MS, GK and WCM over several iterations. All authors approved the final manuscript.Figure S1. Changes in weight within the first two‐years of ART initiation among PWH starting different INSTI‐ drugs compared to those starting PI‐ or NNRTI‐based regimens.Click here for additional data file.Figure S2. Predicted probability of >10% weight gain after two years of ART by age and regimen class.Click here for additional data file.Figure S3. Transition between the BMI categories of underweight (<18.5kg/m2), normal BMI (18.5 to 24.9kg/m2), overweight (25.0 to 29.9kg/m2) and obese (≥30kg/m2) over three years of ART by regimen class.Click here for additional data file.Table S1. Predicted weight  and predicted change in weight compared to baseline for persons with HIV starting different ART regimens.Click here for additional data file.


Elderly patients aged ≥65 years represent a growing population in the perioperative field, particularly orthopedic and vascular surgery. The higher degree of age‐related or comorbid‐dependent vascular alterations renders these patients at risk for hemodynamic complications and likely denote a possible limitation for modern, non‐invasive arterial pressure monitoring devices. The aim was to compare vascular unloading technique‐derived to invasive measurements of systolic (SAP), diastolic (DAP), and mean arterial pressure (MAP) in elderly perioperative patients.This prospective observational study included patients aged ≥65 years scheduled for orthopedic and patients ≥50 years with peripheral artery disease Fontaine stage ≥ II scheduled for vascular surgery, respectively. Invasive radial artery and non‐invasive finger‐cuff (Nexfin system) arterial pressures were recorded before and after induction of general anesthesia and during surgery. Correlation, Bland‐Altman, and concordance analyses were performed. Measurements of arterial pressure were also compared during intraoperative hypotension (MAP <70 mm Hg) and hypertension (MAP >105 mm Hg).Sixty patients with orthopedic  age 77 (5) years) and vascular surgery  were enrolled. Seven hundred data pairs of all patients were analysed and pooled bias and percentage error were: SAP: 14.43 mm Hg, 43.79%; DAP: −2.40 mm Hg, 53.78% and MAP: 1.73 mm Hg, 45.05%. Concordance rates were 84.01% for SAP, 77.87% for DAP, and 86.47% for MAP. Predefined criteria for interchangeability of absolute and trending values could neither be reached in the overall nor in the subgroup analyses orthopedic vs vascular surgery. During hypertension, percentage error was found to be lowest for all pressure values, still not reaching predefined criteria.Arterial pressure monitoring with the vascular unloading technique did not reach criteria of interchangeability for absolute and trending values. Nevertheless, the putatively beneficial use of noninvasive arterial pressure measurements should be further evaluated in the elderly perioperative patient. Written informed consent was obtained from all patients prior to study participation. All study procedures were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.This was a prospective observational cohort study conducted from October 2015 to June 2017 at the Department of Anaesthesiology and Intensive Care Medicine, University Medical Center, Schleswig‐Holstein, Campus Kiel, Kiel, Germany. Inclusion criteria were defined as patients with an age ≥65 years scheduled for orthopedic surgery and ≥50 years with preexisting peripheral artery disease Fontaine stage ≥ II scheduled for (elective or urgent) vascular surgery, respectively. Further inclusion criteria were an American Society of Anesthesiologists (ASA) physical status classification II‐IV and written informed consent for study participation. Exclusion criteria were defined as need for vasopressor support prior to surgery, ASA physical status classification V, cognitive or linguistic barriers and emergency surgery. Types of orthopedic  and vascular surgery  were not further restricted in order to cover a broad spectrum of possible different hemodynamic changes associated with surgical‐ and anesthesia‐related hemodynamic changes and carotid baroreflex sensitivity. The study protocol was approved by the local ethics committee of the Christian‐Albrechts‐University Kiel, Germany (file number: A 135/14) and retrospectively registered with the trial registration number NCT03178097 at 2.2The standard anesthesia monitoring was established as follows: pulse oximetry, electrocardiography, and noninvasive blood pressure measurement taken by a cuff at the upper limb. The arterial line  was placed under local anesthesia in Seldinger technique in the radial artery on the same side as the finger cuff, in accordance to previous study protocols.2.3The study protocol is illustrated in Figure 2.4α = 5%, the minimum required sample size for the effect size of 5/8 = 0.625 was calculated to be at least 44 . AAMI recommends a minimum sample size of 85 patients, although comparisons of continuous, finger‐cuff arterial pressure measurements with an invasive reference method are excluded by this standard.SD of bias/[invasive arterial pressure/2] to quantify the relative differences between both measurement techniques as an additional statistical estimate with acceptable cut‐off values at 14.7% for SAP, 17.5% for DAP, and 18.7% for MAP as reported by Ilies et al.P value of <.05 was considered as statistically significant. Statistical analysis was performed using SPSS Statistics 21 for Windows .The recommended Association for the Advancement of Medical Instrumentation (AAMI) criterion of a mean difference ≤5 mm Hg and associated SD of ≤8 mm Hg3Sixty patients were included in the study with 25 participants undergoing orthopedic and 35 participants vascular surgery. Table 3.1r = .542, P < .001; DAP: r = .407, P < .001; MAP: r = .538, P < .001. According to the Bland‐Altman analysis, Nexfin underestimated SAP and MAP with a bias (SD) of 14.43 (28.24) mm Hg and 1.73 (18.76) mm Hg, respectively and overestimated DAP with a bias of −2.40 (16.49) mm Hg. Thus, the AAMI criterion for interchangeability was not met. For SAP, PE was 43.79%, for DAP 53.78% and for MAP 45.05% exceeding the predefined cut‐off values.Table Table 3.2Table During hypertension, SAP and MAP correlated significantly, whereas no significant correlation could be found for DAP between the Nexfin‐ and invasive reference system. Nexfin consistently overestimated all arterial pressure values during hypertension. Percentage error was found to be lowest during hypertension as opposed to the PE of the whole data sample  but still higher than the predefined cut‐off values. During hypotension, no significant correlation could be shown for any of the three arterial pressure parameters. The bias was 7.86 mm Hg for SAP, −9.44 mm Hg for DAP, and −6.40 mm Hg for MAP. PE was highest during hypotension for all arterial pressure parameters in comparison to the total cohort: 55.57% vs 43.79% for SAP, 76.08% vs 53.78% for DAP, and 60.81% vs 45.05% for MAP. Figure 4In this prospective observational cohort study arterial pressure measurement by the vascular unloading technology (Nexfin system) was compared to the invasive radial arterial line reference method in 60 elderly patients undergoing orthopedic and vascular surgery. We found that the accuracy of the vascular unloading technology during the preoperative and intraoperative phase was not sufficient. The lowest PE of all blood pressure recordings was calculated for SAP during periods of arterial hypertension while the PE was highest for DAP during arterial hypotension, still not reaching predefined cut‐off values. Furthermore, the vascular unloading method did not show an acceptable blood pressure trending capability in our perioperative setting.A number of studies exist comparing the Nexfin technology with invasive arterial pressure measurements in different clinical settings and patient categories, including cardiac,However, systematic evidence is scarce regarding whether the noninvasive vascular‐unloading method provides valid continuous arterial pressure measurements in elderly perioperative patients who exhibit a higher risk of age‐related or comorbid‐dependent vascular disorders. A recent meta‐analysis including 28 studies with 919 patients revealed that the pooled bias (SD) of continuous noninvasive compared with invasive arterial pressure measurements was −1.6 (12.2) mm Hg for SAP, 5.3 (8.3) mm Hg for DAP, and 3.2 (8.4) mm Hg for MAP which would not satisfy the standards of the AAMI guidelines.Our study has some limitations to be addressed. Our study sample size of 60 participants deviates from the current recommendation of the AAMI, the European Society of Hypertension (ESH), and the International Organization for Standardization (ISO) collaboration that at least 85 participants are required for studies validating non‐invasive sphygmomanometers.5In conclusion, noninvasive arterial pressure measurement using the vascular unloading technique (Nexfin finger‐cuff technology) in the perioperative phase of elderly or vascular comorbid patients, respectively was not interchangeable with the gold standard of invasive arterial line measurement. Our findings underline further demand of larger clinical trials to better evaluate the useability of noninvasive measurement devices in this growing proportion of perioperative patients.No external funding was received for this study.All authors have provided information on potential conflicts of interests directly or indirectly related to the work submitted and filled out the ICMJE disclosure forms. All authors declare that they have no conflict of interest.Conceptualization: Gunnar Elke, Jochen RennerData Curation: Phil Klose, Ulf Lorenzen, Gunnar Elke, Jochen RennerFormal Analysis: Phil Klose, Ulf Lorenzen, Christoph Borzikowsky, Matthias Gruenewald, Gunnar Elke, Jochen RennerFunding Acquisition: Not applicableInvestigation: Phil Klose, Ulf Lorenzen, Rouven Berndt, Moritz Hill, Matthias Gruenewald, Gunnar Elke, Jochen RennerMethodology: Phil Klose, Christoph Borzikowsky, Matthias Gruenewald, Gunnar Elke, Jochen RennerProject Administration: Phil Klose, Gunnar Elke, Jochen RennerResources: Phil Klose, Ulf Lorenzen, Rouven Berndt, Christoph Borzikowsky, Moritz Hill, Matthias Gruenewald, Gunnar Elke, Jochen RennerSoftware: Not applicableSupervision: Gunnar Elke, Jochen RennerValidation: Phil Klose, Ulf Lorenzen, Christoph Borzikowsky, Matthias Gruenewald, Gunnar Elke, Jochen RennerVisualization: Phil Klose, Ulf Lorenzen, Gunnar Elke, Jochen RennerWriting ‐ Original Draft Preparation: Phil Klose, Ulf Lorenzen, Gunnar Elke, Jochen RennerWriting ‐ Review and Editing: Phil Klose, Ulf Lorenzen, Rouven Berndt, Christoph Borzikowsky, Moritz Hill, Matthias Gruenewald, Gunnar Elke, Jochen Renner All authors have read and approved the final version of the manuscript. The corresponding author Gunnar Elke confirms that he had full access to all of the data in the study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.The corresponding author Gunnar Elke confirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.