The human genetic epidemiology of COVID-19.

Human genetics can inform the biology and epidemiology of coronavirus disease 2019 (COVID-19) by pinpointing causal mechanisms that explain why some individuals become more severely affected by the disease upon infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Large-scale genetic association studies, encompassing both rare and common genetic variants, have used different study designs and multiple disease phenotype definitions to identify several genomic regions associated with COVID-19. Along with a multitude of follow-up studies, these findings have increased our understanding of disease aetiology and provided routes for management of COVID-19. Important emergent opportunities include the clinical translatability of genetic risk prediction, the repurposing of existing drugs, exploration of variable host effects of different viral strains, study of inter-individual variability in vaccination response and understanding the long-term consequences of SARS-CoV-2 infection. Beyond the current pandemic, these transferrable opportunities are likely to affect the study of many infectious diseases.

Reduced reproductive success is associated with selective constraint on human genes.

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. Although genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known2. Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily owing to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is probably mediated by genetically associated cognitive and behavioural traits, which may mean that male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. Although this genetic association may only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.

There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

Lower Extremity Vascular Injury in the Pediatric Trauma Patient: Management and Outcomes at an Adult Level I Trauma Center.

BACKGROUND: Traumatic vascular injuries of the lower extremity in the pediatric population are uncommon but can result in significant morbidity. The objective of this study is to demonstrate our experience with these injuries by describing patterns of traumatic vascular injury, the initial management, and data regarding early outcomes. METHODS: In total, 506 patients presented with lower extremity vascular injury between January 1, 2009 and January 1, 2021 to Grady Memorial Hospital, an urban, adult Level I trauma center in Atlanta, Georgia. Thirty-two of the 506 patients were aged less than 18 years and were evaluated for a total of 47 lower extremity vascular injuries. To fully elucidate the injury patterns and clinical course in this population, we examined patient demographics, mechanism of injury, type of vessel injured, surgical repair performed, and early outcomes and complications. RESULTS: The median (interquartile range) age was 16 (2) years (range, 3-17 years), and the majority were male (n = 29, 90.6%). Of the vascular injuries identified, 28 were arterial and 19 were venous. Of these injuries, 14 patients had combined arterial-venous injuries. The majority of injuries were the result of a penetrating injury (n = 28, 87.5%), and of these, all but 2 were attributed to gunshot wounds. Twenty-seven vascular interventions were performed by nonpediatric surgeons: 11 by trauma surgeons, 13 by vascular surgeons, 2 by orthopedic surgeons, and 1 by an interventional radiologist. Two patients required amputation: 1 during the index admission and 1 delayed at 3 months. Overall survival was 96.9%. CONCLUSIONS: Vascular injuries as the result of trauma at any age often require early intervention, and we believe that these injuries in the pediatric population can be safely managed in adult trauma centers with a multidisciplinary team composed of trauma, vascular, and orthopedic surgeons with the potential to decrease associated morbidity and mortality from these injuries.

Siloed mentality, health system suboptimization and the healthcare symphony: a Canadian perspective.

Measuring and optimizing a health system is challenging when patient care is split between many independent organizations. For example, patients receive care from their primary care provider, outpatient specialist clinics, hospitals, private providers and, in some instances, family members. These silos are maintained through different funding sources (or lack of funding) which incentivize siloed service delivery. A shift towards prioritizing patient outcomes and keeping the patient at the centre of care is emerging. However, competing philosophies on patient needs, how health is defined and how health is produced and funded is creating and engraining silos in the delivery of health services. Healthcare and health outcomes are produced through a series of activities conducted by diverse teams of health professionals working in concert. Health professionals are continually learning from each patient interaction; however, silos are barriers to information exchange, collaborative evidence generation and health system improvement. This paper presents a systems view of healthcare and provides a systems lens to approach current challenges in health systems. The first part of the paper provides a background on the current state and challenges to healthcare in Canada. The second part presents potential reasons for continued health system underperformance. The paper concludes with a system perspective for addressing these challenges.

Interventional Radiology in Obstetrics and Gynecology: Updates in Women's Health.

Interventional radiology has had an expanding role in women's health over the past few decades, with recent accelerated growth and development. Interventional radiology is fundamental in the treatment of multiple conditions that affect women, including pelvic venous disease, uterine fibroids, and adenomyosis, and in postpartum management. Patient workup, classification, and treatment techniques have continued to evolve as interventional radiology has become more prevalent in the treatment of patients affected by these conditions. The authors provide a review of the pathophysiology of, patient workup for, and treatment of pelvic venous disease and uterine artery embolization for various disease processes. The authors also highlight updates from the past 5-10 years in diagnosis, classification, and treatment strategies. © RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy.

BACKGROUND: Cardiomyocyte hypertrophy is a hallmark of cardiac dysfunction in patients with aortic stenosis (AS), and can be triggered by left ventricular (LV) pressure overload in mice by aortic banding (AB). Syndecan-4 is a transmembrane heparan sulphate proteoglycan which is found increased in the myocardium of AS patients and AB mice. The role of syndecan-4 in cardiomyocyte hypertrophy is not well understood. PURPOSE OF THE STUDY: We developed mice with cardiomyocyte-specific overexpression of syndecan-4 (Sdc4-Tg) and subjected these to AB to examine the role of syndecan-4 in hypertrophy and activation of the pro-hypertrophic calcineurin-NFAT signalling pathway. METHODS AND RESULTS: Sdc4-Tg mice showed exacerbated cardiac remodelling upon AB compared to wild type (WT). At 2-6 weeks post-AB, Sdc4-Tg and WT mice showed similar hypertrophic growth, while at 20 weeks post-AB, exacerbated hypertrophy and dysfunction were evident in Sdc4-Tg mice. After cross-breeding of Sdc4-Tg mice with NFAT-luciferase reporter mice, we found increased NFAT activation in Sdc4-Tg hearts after AB. Immunoprecipitation showed that calcineurin bound to syndecan-4 in Sdc4-Tg hearts. Isolated cardiomyocytes from Sdc4-Tg mice showed alterations in Ca2+ fluxes, suggesting that syndecan-4 regulated Ca2+ levels, and thereby, activating the syndecan-4-calcineurin complex resulting in NFAT activation and hypertrophic growth. Similarly, primary cardiomyocyte cultures from neonatal rats showed increased calcineurin-NFAT-dependent hypertrophic growth upon viral Sdc4 overexpression. CONCLUSION: Our study of mice with cardiomyocyte-specific overexpression of Sdc4 have revealed that syndecan-4 is important for activation of the Ca2+-dependent calcineurin-NFAT signalling pathway, hypertrophic remodelling and dysfunction in cardiomyocytes in response to pressure overload.

No evidence of avian influenza antibodies in two species of raptor nestlings inhabiting Norway.

BACKGROUND: Since 2016, incursions of highly pathogenic avian influenza virus (HPAIV) H5N8 clade 2.3.4.4b have caused unprecedented clinical signs and mortality in white-tailed eagles (WTE; Haliaeetus albicilla) across Europe and have been found to be infecting other raptor species, such as the northern goshawk (NG; Accipiter gentilis). Before this study, no screening of Norwegian raptors had been undertaken. RESULTS: Plasma samples from 43 white-tailed eagle and 29 northern goshawk nestlings, from several locations across Norway were screened for antibodies to avian influenza viruses. No antibodies, and thus, no evidence of AIV exposure, were found in these Norwegian raptors. No clinical signs of AIV were observed in 43 white tailed eagles and 29 northern goshawks. CONCLUSIONS: There are currently no indications that white-tailed eagles and northern goshawks inhabiting Norway are threatened by the recent HPAIV outbreaks in other areas of Europe. Ongoing monitoring should, however, be maintained to detect potential future outbreaks.

Stormwater-quality performance of lined permeable pavement systems.

Three permeable pavements were evaluated for their ability to improve the quality of stormwater runoff over a 22-month period in Madison, Wisconsin. Using a lined system with no internal water storage, permeable interlocking concrete pavers (PICP), pervious concrete (PC), and porous asphalt (PA) were able to significantly remove sediment and sediment-bound pollutant loads from runoff originating from an asphalt parking lot five times larger than the receiving permeable pavement area. Reductions in total suspended solids were similar for all three surfaces at approximately 60 percent. Clogging occurred after approximately one year, primarily due to winter sand application that led to high sediment load in spring runoff. Winter road salt application resulted in high chloride load that was initially attenuated in all three permeable pavements but later released during subsequent spring runoff events. Total phosphorus load was reduced by nearly 20 percent for PICP and PA, and 43 percent for PC. These values were likely tempered by the export of dissolved phosphorus observed in PICP and PA, but not PC. Average removal efficiencies for metals were 40, 42, and 49 percent in PA, PICP, and PC, respectively. A median pH of 10.2 in PC effluent could explain elevated removal efficiency of phosphorus and select metals in PC over PICP and PA (median = 7.5 and 7.8, respectfully) through enhanced precipitation. Elevated pH values in PC may also have led to higher removal efficiencies for select metals than PICP or PA. The environmental benefits as well as potential unintended consequences of stormwater practices like permeable pavement that utilize infiltration as a form of treatment warrant consideration in management of urban runoff.

Defining CT Perfusion Thresholds for Infarction in the Golden Hour and With Ultra-Early Reperfusion.

In this brief report, computed tomography perfusion (CTP) thresholds predicting follow-up infarction in patients presenting 20 to 23 seconds and cerebral blood flow <5 to 7 ml/min-1/(100 g)-1 or relative cerebral blood flow <0.14 to 0.20 optimally predicted the final infarct. These thresholds are stricter than published thresholds.

In ovo transformation of two emerging flame retardants in Japanese quail (Coturnix japonica).

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and Dechlorane Plus (DP) are two chlorinated, alternative flame retardants that have been found in wild birds and bird eggs. Little is known about the fate and effect of these compounds in birds, especially during the vulnerable stages of embryonic development. To investigate the ability of birds to biotransform these compounds, an in ovo exposure experiment with Japanese quail eggs was performed. Quail eggs were injected in the yolk sac with 1000ng/g egg of TDCIPP (2.3 nmol/g ww), DP (1.5 nmol/g ww) or a mixture of both and were then incubated at 37.5°C for 17 days. To get a time-integrated understanding of the in ovo transformation of the compounds, one egg per treatment was removed from the incubator every day and analyzed for TDCIPP and its metabolite bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and/or for DP. By the end of the incubation period, TDCIPP was completely metabolized, while simultaneously BDCIPP was formed. The conversion of the parent compound into the metabolite did not occur proportionally and the concentration of BDCIPP showed a tendency to decrease when TDCIPP became depleted, both indicating that BDCIPP was further transformed into compounds not targeted for analysis. Further untargeted investigations did not show the presence of other metabolites, possibly due to the volatility of the metabolites. On the other hand, the DP concentration did not decrease during egg incubation. This study indicates that within the incubation period, avian embryos are able to biotransform TDCIPP, but not DP.

Use of Noncontrast Computed Tomography and Computed Tomographic Perfusion in Predicting Intracerebral Hemorrhage After Intravenous Alteplase Therapy.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage is a feared complication of intravenous alteplase therapy in patients with acute ischemic stroke. We explore the use of multimodal computed tomography in predicting this complication. METHODS: All patients were administered intravenous alteplase with/without intra-arterial therapy. An age- and sex-matched case-control design with classic and conditional logistic regression techniques was chosen for analyses. Outcome was parenchymal hemorrhage on 24- to 48-hour imaging. Exposure variables were imaging (noncontrast computed tomography hypoattenuation degree, relative volume of very low cerebral blood volume, relative volume of cerebral blood flow ≤7 mL/min·per 100 g, relative volume of Tmax ≥16 s with all volumes standardized to z axis coverage, mean permeability surface area product values within Tmax ≥8 s volume, and mean permeability surface area product values within ipsilesional hemisphere) and clinical variables (NIHSS [National Institutes of Health Stroke Scale], onset to imaging time, baseline systolic blood pressure, blood glucose, serum creatinine, treatment type, and reperfusion status). RESULTS: One-hundred eighteen subjects (22 patients with parenchymal hemorrhage versus 96 without, median baseline NIHSS score of 15) were included in the final analysis. In multivariable regression, noncontrast computed tomography hypoattenuation grade (P<0.006) and computerized tomography perfusion white matter relative volume of very low cerebral blood volume (P=0.04) were the only significant variables associated with parenchymal hemorrhage on follow-up imaging (area under the curve, 0.73; 95% confidence interval, 0.63-0.83). Interrater reliability for noncontrast computed tomography hypoattenuation grade was moderate (κ=0.6). CONCLUSIONS: Baseline hypoattenuation on noncontrast computed tomography and very low cerebral blood volume on computerized tomography perfusion are associated with development of parenchymal hemorrhage in patients with acute ischemic stroke receiving intravenous alteplase.

Longitudinal On-Column Thermal Modulation for Comprehensive Two-Dimensional Liquid Chromatography.

Longitudinal on-column thermal modulation for comprehensive two-dimensional liquid chromatography is introduced. Modulation optimization involved a systematic investigation of heat transfer, analyte retention, and migration velocity at a range of temperatures. Longitudinal on-column thermal modulation was realized using a set of alkylphenones and compared to a conventional valve-modulator employing sample loops. The thermal modulator showed a reduced modulation-induced pressure impact than valve modulation, resulting in reduced baseline perturbation by a factor of 6; yielding a 6-14-fold improvement in signal-to-noise. A red wine sample was analyzed to demonstrate the potential of the longitudinal on-column thermal modulator for separation of a complex sample. Discrete peaks in the second dimension using the thermal modulator were 30-55% narrower than with the valve modulator. The results shown herein demonstrate the benefits of an active focusing modulator, such as reduced detection limits and increased total peak capacity.

129Xe NMR-based sensors: biological applications and recent methods.

Xenon is a first-rate sensor of biological events owing to its large polarizable electron cloud, which induces significant modifications to NMR parameters in response to slight changes in its local environment. The use of xenon as a sensor is of increasing interest for sensitive magnetic resonance imaging, because its signal can be enhanced by several orders of magnitude, mainly by spin-exchange optical pumping. Furthermore, xenon can be vectorized toward targets of interest by using functionalized host systems, which enables their detection at sub-nanomolar concentrations. In association with a new generation of detection methods, this gives rise to a powerful molecular imaging approach, whereby xenon can be delivered systematically several times after the introduction of a functionalized host system.

MR imaging of carotid webs.

PURPOSE: We propose a magnetic resonance (MR) imaging protocol for the characterization of carotid web morphology, composition, and vessel wall dynamics. The purpose of this case series was to determine the feasibility of imaging carotid webs with MR imaging. METHODS: Five patients diagnosed with carotid web on CT angiography were recruited to undergo a 30-min MR imaging session. MR angiography (MRA) images of the carotid artery bifurcation were acquired. Multi-contrast fast spin echo (FSE) images were acquired axially about the level of the carotid web. Two types of cardiac phase resolved sequences (cineFSE and cine phase contrast) were acquired to visualize the elasticity of the vessel wall affected by the web. RESULTS: Carotid webs were identified on MRA in 5/5 (100%) patients. Multi-contrast FSE revealed vessel wall thickening and cineFSE demonstrated regional changes in distensibility surrounding the webs in these patients. CONCLUSION: Our MR imaging protocol enables an in-depth evaluation of patients with carotid webs: morphology (by MRA), composition (by multi-contrast FSE), and wall dynamics (by cineFSE).

Japanese quail (Coturnix japonica) liver and thyroid gland histopathology as a result of in ovo exposure to the flame retardants tris(1,3-dichloro-2-propyl) phosphate and Dechlorane Plus.

Japanese quails (Coturnix japonica) were exposed in ovo to tris(1,3-dichloro-2-propyl) phosphate (TDCIPP; 500 ng/µl), Dechlorane Plus (DP; 500 ng/µl), or a 1:1 mixture of these two to investigate the effects on liver and thyroid gland morphology. Histological examination of 14-day-old quails showed that exposure to TDCIPP or the mixture induced hepatic sinusoidal dilatation. No marked effects were seen for DP alone. In addition, the mixture produced divergence of thyroid gland follicles and proliferation of follicular cells. Our study is the first demonstrating histopathological alterations as a result of exposure during early development to the flame retardants TDCIPP or a TDCIPP-DP mixture suggesting the need for further research efforts to investigate potential adverse health effects associated with exposure to these environmental chemicals in wild birds.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. DESIGN: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorized as deficient (<40 nmol/l), insufficient (40-70 nmol/l) or replete (>70 nmol/l). PATIENTS: A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6-48·3 year), 0·3-56·5 months after TBI (74·5% moderate-severe). MEASUREMENTS: Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE-R), Beck Depression Inventory-II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index. RESULTS: In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE-R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI-II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. CONCLUSION: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.

Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice.

Inflammation is central to heart failure progression. Innate immune signaling increases expression of the transmembrane proteoglycan syndecan-4 in cardiac myocytes and fibroblasts, followed by shedding of its ectodomain. Circulating shed syndecan-4 is increased in heart failure patients, however the pathophysiological and molecular consequences associated with syndecan-4 shedding remain poorly understood. Here we used lipopolysaccharide (LPS) challenge to investigate the effects of syndecan-4 shedding in the heart. Wild-type mice (10mg/kg, 9h) and cultured neonatal rat cardiomyocytes and fibroblasts were subjected to LPS challenge. LPS increased cardiac syndecan-4 mRNA without altering full-length protein. Elevated levels of shedding fragments in the myocardium and blood from the heart confirmed syndecan-4 shedding in vivo. A parallel upregulation of ADAMTS1, ADAMTS4 and MMP9 mRNA suggested these shedding enzymes to be involved. Echocardiography revealed reduced ejection fraction, diastolic tissue velocity and prolonged QRS duration in mice unable to shed syndecan-4 (syndecan-4 KO) after LPS challenge. In line with syndecan-4 shedding promoting immune cell recruitment, expression of immune cell markers (CD8, CD11a, F4/80) and adhesion receptors (Icam1, Vcam1) were attenuated in syndecan-4 KO hearts after LPS. Cardiomyocytes and fibroblasts exposed to shed heparan sulfate-substituted syndecan-4 ectodomains showed increased Icam1, Vcam1, TNFα and IL-1ß expression and NF-κB-activation, suggesting direct regulation of immune cell recruitment pathways. In cardiac fibroblasts, shed ectodomains regulated expression of extracellular matrix constituents associated with collagen synthesis, cross-linking and turnover. Higher syndecan-4 levels in the coronary sinus vs. the radial artery of open heart surgery patients suggested that syndecan-4 is shed from the human heart. Our data demonstrate that shedding of syndecan-4 ectodomains is part of the cardiac innate immune response, promoting immune cell recruitment, extracellular matrix remodeling and mitigating cardiac dysfunction in response to LPS.

Time-Dependent Computed Tomographic Perfusion Thresholds for Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Among patients with acute ischemic stroke, we determine computed tomographic perfusion (CTP) thresholds associated with follow-up infarction at different stroke onset-to-CTP and CTP-to-reperfusion times. METHODS: Acute ischemic stroke patients with occlusion on computed tomographic angiography were acutely imaged with CTP. Noncontrast computed tomography and magnectic resonance diffusion-weighted imaging between 24 and 48 hours were used to delineate follow-up infarction. Reperfusion was assessed on conventional angiogram or 4-hour repeat computed tomographic angiography. Tmax, cerebral blood flow, and cerebral blood volume derived from delay-insensitive CTP postprocessing were analyzed using receiver-operator characteristic curves to derive optimal thresholds for combined patient data (pooled analysis) and individual patients (patient-level analysis) based on time from stroke onset-to-CTP and CTP-to-reperfusion. One-way ANOVA and locally weighted scatterplot smoothing regression was used to test whether the derived optimal CTP thresholds were different by time. RESULTS: One hundred and thirty-two patients were included. Tmax thresholds of >16.2 and >15.8 s and absolute cerebral blood flow thresholds of <8.9 and <7.4 mL·min(-1)·100 g(-1) were associated with infarct if reperfused <90 min from CTP with onset <180 min. The discriminative ability of cerebral blood volume was modest. No statistically significant relationship was noted between stroke onset-to-CTP time and the optimal CTP thresholds for all parameters based on discrete or continuous time analysis (P>0.05). A statistically significant relationship existed between CTP-to-reperfusion time and the optimal thresholds for cerebral blood flow (P<0.001; r=0.59 and 0.77 for gray and white matter, respectively) and Tmax (P<0.001; r=-0.68 and -0.60 for gray and white matter, respectively) parameters. CONCLUSIONS: Optimal CTP thresholds associated with follow-up infarction depend on time from imaging to reperfusion.