Sunnybrook Health Sciences Centre

Background It is an unclear how cholesterol‐lowering statin drugs affect progression of chronic lymphocytic leukemia (CLL). Methods Clinical records of 57 CLL patients were examined to determine how initiating statins in the “watch and wait” phase of management affected disease progression. Results After 6.4 ± 0.6 months, when average low‐density lipoprotein cholesterol levels had been lowered from 3.58 ± 0.11 mM to 2.1 ± 0.06 mM, blood levels of CLL cells and beta‐2‐microglobulin (β2M) increased significantly, accompanied by significant decreases in platelets. Following statin institution, rates of change of blood lymphocytes and β2M increased from 1.55 ± 0.39 × 10⁶ to 3.4 ± 0.68 × 10⁶ cells/mL/month (n = 43) and 0.035 ± 0.011 to 0.055 ± 0.007 μg/mL/month (n = 40), respectively. Conventional first‐line CLL treatment was ultimately required in 37 patients. Conclusions These observations suggest that statins as single agent do not slow and may even modestly stimulate progression of CLL.

Background Unnecessarily prolonged antibiotic durations may contribute to the development of resistance in both humans and animals. Veterinarians need evidence supporting antibiotic treatment durations. This systematic review and meta-analysis aimed to compare the efficacy of shorter durations of antibiotic treatment to longer durations in treating urinary tract infections (UTIs) in dogs and cats. Methods Four databases (MEDLINE, Scopus, EMBASE, and CAB Abstracts) were searched from inception to October 2nd, 2024. Studies that reported the impact of antibiotic treatments of different durations for simple UTIs in dogs or cats and reported a primary outcome of interest, specifically clinical or microbiological resolution of the UTIs, were included. For each study, two reviewers independently screened extracted data and evaluated the risk of bias. Random effects models were used to compare pooled risk ratios of cure rates. Results Of 2,324 studies screened, we identified three studies (two randomized and one nonrandomized controlled trial) which met our inclusion criteria for meta-analysis. Studies examined only 26 animals (9 events) across their short-duration arms and 28 animals (17 events) across long-duration arms. All studies were assessed as having high or serious risk of bias. The pooled risk ratio for cure with short versus longer durations of treatment was 0.55, 95% CI: 0.23–1.27; the evidence was graded as very low certainty. Studies compared 1 to 3-day durations, 3 days to 14-day and 3 days to 21-day durations. Conclusion Based on this data alone, we cannot make conclusions about the efficacy of short compared to long antibiotic durations for treating UTIs in cats and dogs; due to the low numbers of included studies and patients, the confidence intervals for the pooled risk ratio were wide and could be consistent with inferiority or superiority of shorter treatment. Existing evidence supports shorter durations of antibiotics for treating sporadic UTIs in dogs and cats, however this systematic review and meta-analysis highlights that this is still a serious knowledge gap that must be addressed. Studies that examine optimal antibiotic durations for treating UTIs in dogs and cats are urgently needed to support clinical decision-making, inform guidelines, and improve antimicrobial stewardship in veterinary medicine. Systematic review registration Open science framework (https://doi.org/10.17605/OSF.IO/2YJPM).

This study investigates the effects of the anticancer drug docetaxel (DTX) and its timing of administration on tumor development and resultant bone quality in a rodent model, considering both healthy animals and those with osteolytic bone metastases secondary to intra-cardiac injection (d0) of HeLa cells. Healthy and tumor-bearing rats were treated with DTX on d7 or d14 and compared to the control (no treatment) and an additional cohort treated with Zoledronic acid (ZOL). Notably, DTX administration on d7 markedly curtailed tumor growth, as evidenced by bioluminescence and histological analysis, indicating its effectiveness in reducing bone metastases. Bone metastases were more established in animals treated with later DTX administration and ZOL, but still reduced compared to no treatment. When considering bone quality, we found that both the organic and mineral phases of bone are impacted by DTX treatment. Tumor-bearing animals exhibited decreased hydroxyproline/proline ratios reflecting change in collagen metabolism compared to healthy controls, but these decreases were only significant with no treatment or DTX administration on d14. This suggests a positive impact of early DTX treatment similar to ZOL on bone quality from an organic perspective. As well, increased CaMean and CaPeak reflecting the degree of calcification was found in healthy rats treated early with DTX, similar to that seen with ZOL compared to the tumor-bearing treated groups. Overall, early docetaxel administration reduced tumor formation and improved bone quality, suggesting its potential benefit in managing bone metastases.

Infection of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in dairy cows causes severe mastitis and milk production losses. Whether cows can develop protective immunity is unclear. Here we infected three lactating cows with HPAI H5N1 genotype B3.13 via the hindquarters of the udder to mimic intra-mammary infection. Inoculated cows displayed clinical responses consistent with affected dairy herds in the United States including virus shedding almost exclusively in inoculated hindquarters that peaked between Days 2–4 post inoculation and gradually declined by Day 21. Histologically, peak virus shedding in milk corresponded with severe acute necrotic mastitis in the inoculated hindquarters but not in the uninoculated forequarters. Two cows were reinfected with HPAI H5N1 virus at unaffected forequarters following resolution of infection. Secondary inoculation did not result in clinical manifestations or virus shedding in milk. Virus-neutralizing antibodies were detected at Day 14 post inoculation in milk with higher titres observed in the inoculated hindquarters relative to the forequarters. We also detected HPAI H5N1 viral RNA in air samples from animal rooms during routine husbandry activity. These data indicate that primary infection via intra-mammary inoculation can generate protective immunity against bovine HPAI H5N1 virus in dairy cows.

Introduction Mild Behavioral Impairment (MBI) is characterized by later‐life emergent and persistent neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a potential precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) of the default mode network (DMN), executive control network (ECN), and salience network (SN) across three cohorts: mild cognitive impairment due to AD (MCI), cerebrovascular disease (CVD), and Parkinson's disease (PD). Additionally, the effect of CNS medication on NPS‐FC associations was explored. Methods Participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). NPS were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q). We used dual regression to generate subject‐specific whole‐brain FC maps of the DMN, ECN, and SN. Using permutation testing we examined the association between NPS scores and FC maps at baseline ( n = 349) and over a 2‐year period ( n = 225), controlling for age, sex, and years of education. A post‐hoc linear model was used to assess the effect of CNS medication on each significant NPI‐FC association within each group. Results In the MCI group ( n = 73), baseline disturbed nighttime behavior was positively correlated with functional connectivity (FC) between the anterior sensorimotor network. Longitudinally ( n = 46), appetite changes were positively associated with FC between the anterior SN and fusiform gyrus. Disinhibition and apathy correlated with FC between the posterior SN and DMN. In the CVD group ( n = 144), baseline anxiety was negatively associated with FC within the DMN and between the right ECN and DMN in the left hippocampus. Longitudinally ( n = 99), agitation/aggression changes were negatively associated with FC between the right ECN and left anterior cerebellum. Irritability, the most common symptom in both MCI and CVD, did not have identifiable neural correlates, possibly due to its complexity or analysis limitations. In the PD group ( n = 132), baseline disturbed nighttime behavior was positively associated with FC between the right ECN and DMN in the precuneus and left ECN and fusiform gyrus. Longitudinally ( n = 80), changes in nighttime behavior correlated with FC between the left ECN and DMN in the precuneus. CNS medications had no effect on NPI‐FC associations in the MCI group. In the CVD group, the absence of CNS medications was linked to decreased right ECN FC. In the PD group, Parkinson's medications changed the direction of the NPI night‐time score‐FC correlation at both baseline and the 2‐year assessment, with higher scores associated with reduced left ECN FC in medicated individuals. Conclusions In conclusion, our study highlights the critical role of the DMN, ECN, and SN in processing neuropsychiatric symptoms (NPS) across MCI, CVD, and PD populations. We found significant associations between NPS and functional connectivity (FC) within and between these networks. MCI and PD showed positive associations with FC, particularly for disturbed nighttime behavior, while CVD exhibited negative associations, notably with anxiety and agitation. Although irritability was common in both MCI and CVD groups, its neural correlates remain unclear, emphasizing the need for further investigation. These findings support existing literature and pave the way for targeted therapeutic approaches, such as brain stimulation, to alleviate NPS. Additionally, the complex role of CNS medications in modulating NPS and FC warrants further investigation.

Purpose Diagnosing carotid near-occlusion (CNO) with colour duplex ultrasound (CDU) is challenging. We hypothesised that CNO is associated with a reduced distal internal carotid artery (ICA) velocity and aimed to assess if distal velocity is able to diagnose CNO accurately. If not, we aimed to develop CDU rule-out and rule-in criteria to diagnose CNO. Methods This is a prospective cross-sectional study in consecutive participants with suspected ≥ 50% carotid stenosis on CT angiography (CTA). CDU velocities in the common carotid artery, the stenosis and distal to the stenosis were examined. CTAs were assessed for CNO, serving as a reference test. If no CDU parameter was both sensitive and specific for CNO, rule-out (98% sensitive) and rule-in (99% specific) criteria were created. Results Of the 315 included participants with ≥ 50% stenosis, 190 (60%) were conventional ≥ 50% stenosis and 125 (40%) CNO. No CDU parameter was both sensitive and specific for CNO. The best exclusion criteria were stenosis end diastolic velocity (EDV) ≤ 63 cm/s and/or distal peak systolic velocity (PSV) > 23 cm/s, seen in 115 (38%) participants. The best rule-in criteria were stenosis EDV ≥ 280 cm/s and/or distal PSV ≤ 23 cm/s, seen in 35 (12%) participants. Of the remaining participants, 143 (47%) were uncertain (74 CNOs) and 9 (3%) were misdiagnosed as carotid occlusion (all CNOs). Conclusions CDU alone cannot diagnose CNO but can rule in or rule out CNO in half of participants with ≥ 50% stenosis. These criteria are intended for inclusion in an algorithm, sorting cases needing further exams, such as CTA and/or phase-contrast magnetic resonance angiography.

A nurse new to home peritoneal dialysis (PD) undoubtedly has to learn all the steps for continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) procedures, along with basics such as hand hygiene, ordering supplies, disposing of supplies, recognizing signs and symptoms of peritonitis. However, it is not always clear what else the new PD nurse needs to know in order to successfully teach a patient all that a patient (and care partner) starting home PD training need to know, as well as to support that patient overtime once the patient is performing PD at home. To answer this question, using a modified Delphi technique, members of the International Society for Peritoneal Dialysis (ISPD) Nursing and Allied Health Professional Committee identified the top 10 practice advice (tips) these nurse members thought all new home PD nurses should know and be aware of. For each tip, we justified the importance of the tip and how it could be implemented. The 10 tips were quite varied and highlighted both the breadth and the depth of knowledge a new PD nurse needs to acquire over and above basic knowledge and skills such as performing CAPD and APD and recognizing signs and symptoms of peritonitis. The members of the ISPD Nursing and Allied Health Professional Committee who compiled this list of the top 10 tips, believe that through understanding the importance, justification, and implementation of each of these tips, the nurse new to a home PD program can, in turn, appreciate more how to individualize home PD training sessions, improve the quality of life for patients on PD, as well as extend the patients’ time on PD.

There is a continuing need for improved preclinical mouse models of cancer that more accurately predict therapy outcomes for future clinical translation. Luciferase and bioluminescence have long been utilized to generate models conducive to non-invasive imaging to monitor tumor growth, disease progression and response to therapy. However, luciferase, as well as fluorescent reporter proteins, are highly immunogenic, limiting their use in some syngeneic tumor models in immunocompetent mice. Here, we described the utility of transgenic mice engineered to have tolerance to luciferase and several other reporter proteins, known as Tol mice, in cancer immunology research. Tumor cell lines expressing both luciferase and GFP were completely rejected in wild-type mice but maintained robust growth in Tol mice. Additionally, Tol mice allowed the development of an experimental brain metastasis model and a post-surgical resection spontaneous metastasis model. Importantly, even when certain cell lines carrying reporter proteins successfully formed tumors in immunocompetent wild-type mice, underlying immunity existed that could be reinvigorated by immune checkpoint inhibitors. Therefore, caution is needed when using such models in wild-type mice as exaggerated effects may be induced by immunotherapy. Tol mice circumvent this problem and will likely widen the number of orthotopic and metastatic tumor models that can be used in immunotherapy studies in both C57Bl/6 and BALB/c mice.

Background Testicular germ cell tumours (TGCTs) are the most common malignancy in men 15-35 years of age. Management options for men with TGCTs include surgery, radiation and/or chemotherapy. Given TGCTs’ excellent survival, most patients live long enough to experience delayed treatment toxicities, warranting careful consideration of therapeutic decisions. An important outcome of interest is the development of secondary malignant neoplasms (SMNs). Methods A systematic literature search was conducted through a combination of database searches (Medline, EMBASE, and Cochrane library) and manual review. Studies evaluating the incidence of SMNs in patients following treatment for TGCTs were identified. Our primary outcome was the diagnosis of any non-germ cell SMN following treatment, compared to the general population. Meta-analyses were performed using random-effects models, with outcomes reported as standardized incidence ratios (SIR). Strength of evidence was evaluated using the GRADE framework. Results Twenty-one studies including 88,863 patients with 5,180 SMNs were included. Median follow-up was 12.5 years. The incidence of non-germ cell SMNs following definitive treatment of TGCTs varied by treatment modality. Surgery alone was not associated with an increased risk (SIR: 0.99, 95% CI: 0.84–1.17); radiation (SIR: 1.66, 95% CI: 1.43–1.93), chemotherapy (SIR: 1.65, 95% CI: 1.39–1.96), and combined chemotherapy and radiation (SIR: 2.73, 95% CI: 2.23–3.33) were associated with a moderate to large increase in risk. There was low to moderate certainty in quality of evidence by GRADE framework. Conclusions Chemotherapy, radiation, and their combination are associated with an increased risk of non-germ cell SMNs after the treatment of TGCTs.

Importance Generic health utility instruments lack the discriminative ability to differentiate among health states in patients after head and neck cancer treatment. Objective To develop, validate, and valuate a head and neck cancer−specific health utility measure. Design, Setting, and Participants This psychometric study comprised 2 phases to develop and validate a health utility instrument. The first phase, development and validation, occurred from January 2021 to August 2022. An expert panel selected disease-specific quality-of-life instruments as the basis for a new utility instrument. Two datasets (n = 458 and 493) were used to establish dimension structure through exploratory factor analysis, and to select items using Rasch and psychometric criteria and expert opinion. Discriminative validity of the new instrument was tested by comparing scores for different disease severities (patients with and without gastrostomy and tracheostomy tubes). The second phase, valuation, was conducted from January 2023 to January 2024 in a quaternary referral center with healthy participants. Participants completed time−trade-off exercises for 100 sampled health states and were randomized to discovery and validation sets (80:20). Using a repeated measures model, a scoring algorithm to predict utilities of health states within the instrument was created in the discovery set and tested in both sets. Data were analyzed from January 2022 to December 2023. Intervention Participants performed time−trade-off exercises for various states. Main Outcomes and Measures Discriminative validity (first phase) and the mean absolute differences of predicted and observed utilities (second phase). Results The European Organization for Research and Treatment of Cancer’s Quality of Life Questionnaire−Core 30 and its Head and Neck module 43 were selected by the expert panel and used as the basis instruments. Exploratory factor analysis established 8 dimensions, with 1 item selected per dimension. Of the 488 respondents, 84 with gastrostomy and/or tracheostomy tubes reported lower scores for 7 of the 8 items. In the second phase, 2497 valuations were performed by 250 healthy participants (mean [SD] age, 42.4 [16.5] years; 166 [66%] females). The scoring algorithm produced mean absolute differences between predicted and observed utilities of 0.041 (95% CI, 0.034-0.047) and 0.082 (95% CI, 0.065-0.100) in the discovery and validation sets, respectively. Conclusions and Relevance This psychometric study developed a new head and neck cancer-specific utility measure, the HNC-8D (Head and Neck Cancer−8 Dimensions). The instrument demonstrated predictive accuracy for measuring health utility and can be used to differentiate health utility states following head and neck cancer treatment.

Objective We sought to determine the clinical features of hemiplegic cerebral palsy associated with perinatal arterial ischemic stroke or periventricular venous infarction. Methods We studied children with hemiplegic cerebral palsy enrolled at 9 rehabilitation centers across Ontario. We compared children with underlying perinatal arterial ischemic stroke or periventricular venous infarction on clinically acquired brain imaging. Analysis also included prenatal (maternal, prenatal/gestational) and perinatal (obstetrical, neonatal) clinical features collected from birth records and standardized parent interviews. Results The 144 children with hemiplegic cerebral palsy (62% male) included 95 with perinatal arterial ischemic stroke and 49 with periventricular venous infarction. In this cohort of children with hemiplegic cerebral palsy, we found neonatal systemic thrombosis (ie, blood clots in the body) ( P = .05), emergency cesarean section ( P = .05), and neonatal seizures ( P = .01) to be clinical features associated with hemiplegic cerebral palsy in children with perinatal arterial ischemic stroke more often than periventricular venous infarction. Preterm delivery rates were similar for perinatal arterial ischemic stroke and periventricular venous infarction. Conclusion We determined clinical features associated with the 2 most typical forms of focal ischemic brain injury in children with hemiplegic cerebral palsy, including mode of delivery emergency cesarean section, neonatal seizures and systemic thrombosis. These findings provide further insight and support for existing findings about focal brain injury patterns leading to hemiplegic cerebral palsy in children.

Background Although deep brain stimulation of the subthalamic nucleus (STN-DBS) induces motor benefits in people with Parkinson’s disease (PwPD), its effect on motor axial symptoms (e.g., postural instability, trunk posture alterations) and gait impairments (e.g., freezing of gait) is still ambiguous. Physical therapy (PT) effectively complements pharmacological treatment to improve postural stability, gait performance, and other dopamine-resistant symptoms (e.g. freezing of gait) in the general population with PD. Despite the positive potential of combined PT and STN-DBS surgery, scientific results are still lacking. We therefore involved worldwide leading experts on DBS and motor rehabilitation in PwPD in a consensus Delphi panel to define the current level of PT recommendation following STN-DBS surgery. Methods After summarizing the few available findings through a systematic scoping review, we identified clinically and academically experienced DBS clinicians (n = 21) to discuss the challenges related to PT following STN-DBS. A 5-point Likert scale questionnaire was used and based on the results of the systematic review, thirty-nine questions were designed and submitted to the panel–half related to general considerations on PT following STN-DBS, and half related to PT treatments. Results Despite the low-to-moderate quality of data, the few available rehabilitation studies suggested that PT could improve dynamic and static balance, gait performance and posture in the population with PD receiving STN-DBS. Similarly, the panellists strongly agreed that PT might help improve motor symptoms and quality of life, and it may be prescribed to maximize the effects of stimulation. The experts agreed that physical therapists could be part of the multidisciplinary team taking care of the patients. Also, they agreed that conventional PT, but not massage or manual therapy, should be prescribed because of the specificity of STN-DBS implantation. Conclusions Although RCT evidence is lacking, upon Delphi panel, PT for PwPD receiving STN-DBS can be potentially useful to maximize clinical improvement. However, more research is needed, with RCTs and well-designed studies. The rehabilitation and DBS community should expand this area of research to create guidelines for PT following STN-DBS. Graphical abstract

Individualized transcranial magnetic stimulation (TMS) targeting using functional connectivity analysis of functional magnetic resonance imaging (fMRI) has been demonstrated to be advantageous in inducing neuroplasticity. However, how this approach can benefit modulating the episodic memory function supported by the hippocampal network remains elusive. We use the resting‐state fMRI data from a large cohort to reveal tentative TMS targets at cortical regions within the hippocampal network. Functional MRI from 1,133 individuals in the Human Connectome Project was used to analyze the hippocampal network using seed‐based functional connectivity. Using a weighted sum of time series at the cortex, we identified the average centroids of individualized targets at the medial prefrontal cortex (mPFC) and posterior parietal cortices (PPCs) at (−10, 49, 7) and (−40, −67, 30) in the left hemisphere, respectively. The mPFC and PPC coordinate at the right hemispheres are (11, 51, 6) and (48, −59, 24) in the right hemisphere, respectively. Centroids of the individualized functional connectivity at the mPFC and PPC were reproducible between sessions with separations in average about 2 and 4 mm, respectively. These separations were significantly smaller than the distance to average functional connectivity centroids (~10 mm) and atlas coordinate (~20 mm). These coordinates can be reliably identified (> 90% of individuals) using cortical “seedmaps.” Our results suggest candidate TMS target coordinates to modulate the hippocampal function.

Background Early detection of reduced stroke volume (SV) or cardiac output (CO) may expedite resuscitative interventions during traumatic hemorrhage; corrected carotid artery flow time (ccFT) has been proposed as a surrogate for SV during blood volume loss. Study Design and Methods We conducted a prospective cohort study to assess the feasibility of using a wireless, wearable Doppler ultrasound capable of measuring ccFT in traumatically injured patients at a level 1 trauma center. A convenience sample of 33 patients was enrolled. We assessed device placement, data transfer and capture, and signal quality by assessing the ability to capture at least 15 consecutive cardiac cycles in the minute prior to blood pressure monitor cycling. A post hoc analysis examined ccFT variations between transfused and non‐transfused patients. Results Device placement succeeded in 94% of patients ( n = 31) and the data were captured and transferred from all 31. The consecutive cardiac cycles before blood pressure measurement exceeded 15 ( p = .015) in 93% of patients ( n = 28). We observed ccFT below 270 ms and longer time spent under this threshold during resuscitation in transfused patients. Patients with low ccFT experienced more severe injuries and longer hospital and ICU stays. Discussion This is the first study that demonstrates the feasibility of using a wearable Doppler ultrasound in trauma patients on admission to the trauma bay. Although findings suggest that ccFT could serve as an early marker of hemodynamic compromise, further large‐scale, multicenter studies are needed to validate its predictive value and clinical utility in guiding trauma resuscitation.

Background Assessing older drivers’ fitness-to-drive (FTD) is challenging, with decisions impacting mobility and health. This study aimed to validate the Candrive older driver risk stratification tool (RST) for screening medical FTD in an independent cohort of older adults from the Ozcandrive 8-year prospective study. Methods A convenience sample of drivers aged 75 and older residing in Melbourne, Australia completed the Candrive assessments. Their vehicles were instrumented to collect vehicle and Global Positioning System (GPS) data, including trip distance. The first four years of Ozcandrive data were analysed. The primary outcome measure was self-reported at-fault collisions, adjusted per 10,000 kilometers driven. Collision risk status was modelled using Generalized Estimating Equations with Poisson regression using predetermined Candrive RST predictor variables. Results A total of 257 older drivers (70.8% male) were recruited with an average age at study enrollment of 79.7 years (Standard Deviation (SD) = 3.5). Of the 755 adjusted person-years of driving, 74.1% were in the Low risk category (vs. original sample, Candrive: 74.8%) and 10.5% were in the Low-Medium risk category (Candrive: 9.3%). Only 15.4% were in the Medium-High risk category (Candrive: 15.9%), where the relative risk for self-reported at-fault collisions was 1.79 (95% confidence interval [CI]= 1.06-3.03) compared to the Low risk category. Conclusions This study demonstrates an association between self-reported at-fault collisions and Candrive RST scores. This result is promising given the primary outcome measure differed from the original Candrive study that used police-reported, at-fault collisions, and supports Candrive RST’s use by healthcare providers when initiating FTD conversations.

Cerebrovascular reactivity (CVR) imaging is used to assess the vasodilatory capacity of cerebral blood vessels. While blood flow (CVRCBF), blood velocity (CVRv), and preferably blood volume changes (CVRCBV) are used to represent physiological CVR, quantifying these measures is fraught with acquisition challenges in humans. Consequently, blood oxygenation level-dependent (BOLD)-MRI CVR (CVRBOLD) is the most widely used MRI-based CVR method, even though it arguably provides the most indirect estimation of CVR. In this paper, we sought to holistically address the quantitative capacity and shortcomings of CVRBOLD. To do so, we developed a CVRBOLD simulation framework and, together with data from the CVRBOLD literature, addressed whether and to what extent CVRBOLD accurately reflects CVR, and with which parameters CVRBOLD varies most. In short, we show the following: CVRBOLD does not necessarily correspond to physiological measures of CVR and depends on physiological (e.g., hematocrit) and acquisition (e.g., field strength) parameters; CVRBOLD is dependent on the stimulus protocol (e.g., breath-holding vs controlled hypercapnia) chosen to elicit a vasoactive response; resting-state CVRBOLD does not necessarily reflect breath-hold CVRBOLD, likely due to confounding neuronal activity; in stenotic disease and steal physiology, CVRBOLD results from a combination of factors which do not necessarily reflect the underlying CVR. We are confident that this work will provide researchers and clinicians with invaluable insights and advance the field of cerebrovascular imaging by enabling more accurate quantification of CVR in both health and disease.