Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance.

ABCG2 is an important ATP-binding cassette transporter impacting the absorption and distribution of over 200 chemical toxins and drugs. ABCG2 also reduces the cellular accumulation of diverse chemotherapeutic agents. Acquired somatic mutations in the phylogenetically conserved amino acids of ABCG2 might provide unique insights into its molecular mechanisms of transport. Here, we identify a tumor-derived somatic mutation (Q393K) that occurs in a highly conserved amino acid across mammalian species. This ABCG2 mutant seems incapable of providing ABCG2-mediated drug resistance. This was perplexing because it is localized properly and retained interaction with substrates and nucleotides. Using a conformationally sensitive antibody, we show that this mutant appears "locked" in a non-functional conformation. Structural modeling and molecular dynamics simulations based on ABCG2 cryo-EM structures suggested that the Q393K interacts with the E446 to create a strong salt bridge. The salt bridge is proposed to stabilize the inward-facing conformation, resulting in an impaired transporter that lacks the flexibility to readily change conformation, thereby disrupting the necessary communication between substrate binding and transport.

A restatement of the natural science evidence base concerning grassland management, grazing livestock and soil carbon storage.

Approximately a third of all annual greenhouse gas emissions globally are directly or indirectly associated with the food system, and over a half of these are linked to livestock production. In temperate oceanic regions, such as the UK, most meat and dairy is produced in extensive systems based on pasture. There is much interest in the extent to which such grassland may be able to sequester and store more carbon to partially or completely mitigate other greenhouse gas emissions in the system. However, answering this question is difficult due to context-specificity and a complex and sometimes inconsistent evidence base. This paper describes a project that set out to summarize the natural science evidence base relevant to grassland management, grazing livestock and soil carbon storage potential in as policy-neutral terms as possible. It is based on expert appraisal of a systematically assembled evidence base, followed by a wide stakeholders engagement. A series of evidence statements (in the appendix of this paper) are listed and categorized according to the nature of the underlying information, and an annotated bibliography is provided in the electronic supplementary material.

Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Late lesion growth following endovascular therapy: is 24 hours too early to assess acute infarct size including the effects of secondary injury?

Introduction Stroke lesion volume on MRI or CT provides objective evidence of tissue injury as a consequence of ischemic stroke. Measurement of "final" lesion volume at 24hr following endovascular therapy (post-EVT) has been used in multiple studies as a surrogate for clinical outcome. However, despite successful recanalization, a significant proportion of patients do not experience favorable clinical outcome. The goals of this study were to quantify lesion growth during the first week after treatment, identify early predictors, and explore the association with clinical outcome. Methods This is a prospective study of stroke patients at two centers who met the following criteria: i) anterior large vessel occlusion (LVO) acute ischemic stroke, ii) attempted EVT, and iii) had 3T MRI post-EVT at 24hr and 5-day. We defined "Early" and "Late" lesion growth as ≥10mL lesion growth between baseline and 24hr DWI, and between 24hr DWI and 5-day FLAIR, respectively. Complete reperfusion was defined as >90% reduction of the volume of tissue with perfusion delay (Tmax>6sec) between pre-EVT and 24hr post-EVT. Favorable clinical outcome was defined as modified Rankin scale (mRS) of 0-2 at 30 or 90 days. Results One hundred twelve patients met study criteria with median age 67 years, 56% female, median admit NIHSS 19, 54% received IV or IA thrombolysis, 66% with M1 occlusion, and median baseline DWI volume 21.2mL. Successful recanalization was achieved in 87% and 68% had complete reperfusion, with an overall favorable clinical outcome rate of 53%. Nearly two thirds (65%) of the patients did not have Late lesion growth with a median volume change of -0.3mL between 24hr and 5-days and an associated high rate of favorable clinical outcome (64%). However, ~1/3 of patients (35%) did have significant Late lesion growth despite successful recanalization (87%: 46% mTICI 2b/ 41% mTICI 3). Late lesion growth patients had a 27.4mL change in Late lesion volume and 30.1mL change in Early lesion volume. These patients had an increased hemorrhagic transformation rate of 68% with only 1 in 3 patients having favorable clinical outcome. Late lesion growth was independently associated with incomplete reperfusion, hemorrhagic transformation, and unfavorable outcome. Conclusion Approximately 1 out of 3 patients had Late lesion growth following EVT, with a favorable clinical outcome occurring in only 1 out of 3 of these patients. Most patients with no Early lesion growth had no Late lesion growth. Identification of patients with Late lesion growth could be critical to guide clinical management and inform prognosis post-EVT. Additionally, it can serve as an imaging biomarker for the development of adjunctive therapies to mitigate reperfusion injury.

Clinical and imaging findings associated with preservation of knee joint health over 8 years in individuals aged 65 and over: data from the OAI.

OBJECTIVE: While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. METHODS: This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. RESULTS: Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. CONCLUSION: Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

Effect of weight loss on knee joint synovitis over 48 months and mediation by subcutaneous fat around the knee: data from the Osteoarthritis Initiative.

BACKGROUND: Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. METHODS: We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (< ± 3% change, n = 117) over 48 months matched for age and sex. In magnetic resonance imaging (MRI) at baseline and 48 months, effusion-synovitis and Hoffa-synovitis using the MRI Osteoarthritis Knee Score (MOAKS) and average joint-adjacent SCF (ajSCF) were assessed. Odds-ratios (ORs) for synovitis progression over 48 months (≥ 1 score increase) were calculated in logistic regression models adjusting for age, sex, baseline BMI, Physical Activity Scale for the Elderly (PASE), and baseline SCF measurements. Mediation of the effect of weight loss on synovitis progression by local SCF change was assessed. RESULTS: Odds for effusion-synovitis progression decreased with weight loss and ajSCF decrease (odds ratio [OR] = 0.61 and 0.56 per standard deviation [SD] change, 95% confidence interval [CI] 0.44, 0.83 and 0.40, 0.79, p = 0.002 and 0.001, respectively), whereas odds for Hoffa-synovitis progression increased with weight loss and ajSCF decrease (OR = 1.47 and 1.48, CI 1.05, 2.04 and 1.02, 2.13, p = 0.024 and 0.038, respectively). AjSCF decrease mediated 39% of the effect of weight loss on effusion-synovitis progression. CONCLUSIONS: Effusion-synovitis progression was slowed by weight loss and decrease in local subcutaneous fat. Hoffa-synovitis characterized by fluid in the infrapatellar fat pad increased at the same time, suggesting a decreasing fat pad rather than active synovitis. Decrease in local subcutaneous fat partially mediated the systemic effect of weight loss on synovitis.

Thigh muscle and fat volumes are associated with knee cartilage abnormalities and bone marrow edema-like lesions: data from the osteoarthritis initiative.

OBJECTIVE: To investigate the associations of thigh muscle and fat volumes with structural abnormalities on MRI related to knee osteoarthritis. MATERIALS AND METHODS: MRI studies of the thighs and knees from 100 individuals were randomly selected from the Osteoarthritis Initiative Cohort. Whole Organ MR Scoring (WORMS) and effusion-synovitis scoring were performed in all knee MRI. Thigh muscles, intermuscular fat, and subcutaneous fat were manually segmented in 15 consecutive MR thigh images. Radiographic Kellgren-Lawrence grades (KLG) were also obtained in all knee radiographs. Independent t-tests were used to investigate the associations between thigh muscle and fat volumes, and sex. Mixed-effects analyses were obtained to investigate the associations between thigh muscle and fat volumes, KLG, WOMAC pain score, cartilage and bone marrow WORMS, as well as effusion-synovitis scores. RESULTS: Women had higher subcutaneous fat volume than men (616.82 vs. 229.13 cm3, p < 0.01) and men had higher muscle volumes than women (p < 0.01). Quadriceps (coef = -2.15, p = 0.01) and vastus medialis (coef = -1.84, p = 0.03) volumes were negatively associated with the WORMS cartilage scores. Intermuscular fat volume (coef = 0.48, p = 0.01) was positively associated with WORMS bone marrow edema-like lesion (BMEL) scores. The quadriceps (coef = -0.99, p < 0.01) and hamstring (coef = -0.59, p = 0.01) volumes were negatively associated with WORMS BMEL scores. No evidence of an association was found between thigh muscle and fat volumes with KLG and effusion-synovitis grading (p > 0.05). CONCLUSION: Increased quadriceps and hamstring volumes were negatively associated with cartilage lesion and BMEL scores while no evidence of an association was found between thigh muscle and fat volumes, and radiographic knee osteoarthritis or effusion-synovitis grading.

To Know Me Is to Exonerate Me: Appeals to Character in Defense of the Willowbrook Hepatitis Study.

The Willowbrook Hepatitis Study is one of the best-known examples of unethical medical research, but the research has always had defenders. One of the more intriguing defenses continually used was that critics did not know the researchers on the study and, therefore, could not assess their ethics. This essay traces the appeal to the researchers' characters across published research and archival sources from the 1960s through today. These appeals reflect the observation as old as Aristotle that one of the most potent modes of persuasion is ethos or character. The specific types of character in these appeals develop out of the paternalistic nature of clinical and research practice in the mid-twentieth century. If the individual physician is the locus of medical judgment, then the physician's character becomes a key concern for bioethics. These appeals still appear and have implications for bioethics in the present day.

Analogies in Genomics Policymaking: Debates and Drawbacks.

The analogy between genomics and imaging has been an important touchstone in the debate on how secondary findings should be handled in both clinical and research genomics contexts. However, a critical eye is needed to understand whether an analogy like this one provides an adequate basis for policymaking in genomics. Genomics and imaging are undoubtedly similar in certain ways, but whether that similarity is adequate to justify adopting identical policies is a task that requires further analysis. This is highlighted by the fact that secondary findings are produced in other domains of medicine and public health, such as newborn screening programs, routine laboratory panels, and antibiotic sensitivity testing, and that the practices for handling secondary findings in each of these areas are different. These examples demonstrate that medicine has no single comprehensive policy or set of practices for managing secondary findings. Analogies to imaging, newborn screening, routine testing panels, and antibiotic sensitivity testing all lead to different policy options for genomics. In this piece we argue that analogies are a powerful way of driving policy discussions by rendering two different areas of medical practice similar, but an overdependence on a single analogy risks limiting policy discussions in potentially deleterious ways.

Associations between weight change, knee subcutaneous fat and cartilage thickness in overweight and obese individuals: 4-Year data from the osteoarthritis initiative.

OBJECTIVE: To assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness. DESIGN: Individuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)). RESULTS: Individuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p < 0.001) than controls; individuals who gained weight had significantly greater joint-adjacent SCF than controls (beta range: -1.4 to -3.9 mm, p < 0.001). No statistically significant associations were found between weight change and cartilage thickness change. However, increases in joint-adjacent SCF over 4 years were significantly associated with decreases in cartilage thickness (p = 0.04). CONCLUSIONS: Weight change was associated with joint-adjacent SCF, but not with change in cartilage thickness. However, 4-year increases in joint-adjacent SCF were associated with decreases in cartilage thickness independent of baseline BMI and weight change group.

Impact of Sustained Synovitis on Knee Joint Structural Degeneration: 4-Year MRI Data from the Osteoarthritis Initiative.

BACKGROUND: Synovial inflammation is a risk factor for osteoarthritis (OA). But to date, there is limited information on how inflammation impacts progression of knee OA. PURPOSE: To investigate how sustained synovitis, assessed with semi-quantitative magnetic resonance imaging (MRI) scores, impacts progression of knee degenerative changes over 4 years. STUDY TYPE: Retrospective cohort study. SUBJECTS: In 249 participants (N = 132 women [53%]), from the Osteoarthritis Initiative (OAI) two definitions for synovitis were used resulting in two groups of participants with sustained synovitis at baseline, 2-year, and 4-year follow-up (N = 80 and N = 132), and two groups without synovitis at all three time points (N = 81 and N = 47). FIELD STRENGTH/SEQUENCE: 3 T intermediate-weighted (IW) turbo spin-echo (TSE) sequence and three-dimensional (3D) dual-echo steady-state (DESS) sequence. ASSESSMENT: Synovitis was scored semi-quantitatively using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS), MRI Osteoarthritis Knee Score (MOAKS), and synovial proliferation score (SPS). Two MRI-based definitions of synovitis were used: (i) score ≥2 based on cumulative score of MOAKS and ACLOAS, and (ii) score ≥3 based on the cumulative score of ACLOAS, MOAKS, and SPS. Changes in structural abnormalities from baseline to year 4 measured using the whole-organ MRI score (WORMS) were defined as outcomes. STATISTICAL TESTS: Linear regression models were used to compare the differences in longitudinal changes in WORMS scores between participants with and without sustained synovitis for each definition of sustained synovitis. A P-value of <0.05 was considered statistically significant. RESULTS: Significantly higher rates of progression were found in participants with synovitis for patellar (Beta coeff. = 0.29) and medial tibial cartilage abnormalities (Beta coeff. = 0.29) for definition (i). For definition (ii), patellar (Beta coeff. = 0.36) and medial femoral cartilage (Beta coeff. = 0.30) abnormalities demonstrated significant differences. DATA CONCLUSION: Greater progression of structural degenerative disease was observed in individuals with sustained synovitis compared to those without sustained synovitis, suggesting that sustained synovitis is associated with progressive OA. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The fraction of life years lost after diagnosis (FLYLAD): a person-centred measure of cancer burden.

BACKGROUND: Cancer control initiatives are informed by quantifying the capacity to reduce cancer burden through effective interventions. Burden measures using health administrative data are a sustainable way to support monitoring and evaluating of outcomes among patients and populations. The Fraction of Life Years Lost After Diagnosis (FLYLAD) is one such burden measure. We use data on Aboriginal and non-Aboriginal South Australians from 1990 to 2010 to show how FLYLAD quantifies disparities in cancer burden: between populations; between sub-population cohorts where stage at diagnosis is available; and when follow-up is constrained to 24-months after diagnosis. METHOD: FLYLADcancer is the fraction of years of life expectancy lost due to cancer (YLLcancer) to life expectancy years at risk at time of cancer diagnosis (LYAR) for each person. The Global Burden of Disease standard life table provides referent life expectancies. FLYLADcancer was estimated for the population of cancer cases diagnosed in South Australia from 1990 to 2010. Cancer stage at diagnosis was also available for cancers diagnosed in Aboriginal people and a cohort of non-Aboriginal people matched by sex, year of birth, primary cancer site and year of diagnosis. RESULTS: Cancers diagnoses (N = 144,891) included 777 among Aboriginal people. Cancer burden described by FLYLADcancer was higher among Aboriginal than non-Aboriginal (0.55, 95% CIs 0.52-0.59 versus 0.39, 95% CIs 0.39-0.40). Diagnoses at younger ages among Aboriginal people, 7 year higher LYAR (31.0, 95% CIs 30.0-32.0 versus 24.1, 95% CIs 24.1-24.2) and higher premature cancer mortality (YLLcancer = 16.3, 95% CIs 15.1-17.5 versus YLLcancer = 8.2, 95% CIs 8.2-8.3) influenced this. Disparities in cancer burden between the matched Aboriginal and non-Aboriginal cohorts manifested 24-months after diagnosis with FLYLADcancer 0.44, 95% CIs 0.40-0.47 and 0.28, 95% CIs 0.25-0.31 respectively. CONCLUSION: FLYLAD described disproportionately higher cancer burden among Aboriginal people in comparisons involving: all people diagnosed with cancer; the matched cohorts; and, within groups diagnosed with same staged disease. The extent of disparities were evident 24-months after diagnosis. This is evidence of Aboriginal peoples' substantial capacity to benefit from cancer control initiatives, particularly those leading to earlier detection and treatment of cancers. FLYLAD's use of readily available, person-level administrative records can help evaluate health care initiatives addressing this need.

Child protection contact among children of culturally and linguistically diverse backgrounds: A South Australian linked data study.

AIM: To describe the cumulative incidence of child protection (CP) system contact, maltreatment type, source of reports to age 7 years, and socio-demographic characteristics for culturally and linguistically diverse (CALD) Australian children. METHODS: We used CP, education, health, and birth registrations data for children followed from birth up to age 7 from the South Australian Better Evidence, Better Outcomes, Linked Data (SA BEBOLD) platform. PARTICIPANTS: SA born children enrolled in their first year of school from 2009 to 2015 (n = 76 563). CALD defined as non-Aboriginal or Torres Strait Islander, spoken language other than English, Indigenous or Sign, or had at least one parent born in a non-English speaking country. OUTCOMES MEASURES: For CALD and non-CALD children, we estimated the cumulative incidence (risk) of CP contacts up to age 7, relative risk and risk differences for all levels of CP contact from notification to out-of-home care (OOHC), primary maltreatment type, reporter type, and socio-economic characteristics. Sensitivity analyses explored different population selection criteria and CALD definitions. RESULTS: By age 7, 11.2% of CALD children had 'screened-in' notifications compared to 18.8% of non-CALD (risk difference [RD] 7.6 percentage points (95% confidence interval: 6.9-8.3)), and 0.6% of CALD children experienced OOHC compared to 2.2% of non-CALD (RD 1.6 percentage points (95% confidence interval: 1.3-1.8)). Emotional abuse was the most common substantiated maltreatment type for CALD and neglect for non-CALD. Among both groups, the most common reporter sources were police and education sector. Socio-economic characteristics were broadly similar. Sensitivity analyses results were consistent with primary analyses. CONCLUSION: By age 7, CALD children had lower risk of contact with all levels of CP. Estimates based on primary and sensitivity analyses suggested CALD children were 5-9 percentage points less likely to have a report screened-in, and from 1.0 to 1.7 percentage points less likely to have experienced OOHC.

The effect of interactions between BMI and sustained depressive symptoms on knee osteoarthritis over 4 years: data from the osteoarthritis initiative.

BACKGROUND: To assess the compound effects of BMI and sustained depressive symptoms on changes in knee structure, cartilage composition, and knee pain over 4 years using statistical interaction analyses. METHODS: One thousand eight hundred forty-four individuals from the Osteoarthritis Initiative Database were analyzed at baseline and 4-year follow-up. Individuals were categorized according to their BMI and presence of depressive symptoms (based on the Center for Epidemiological Studies Depression Scale (threshold≥16)) at baseline and 4-year follow-up. 3 T MRI was used to quantify knee cartilage T2 over 4 years, while radiographs were used to assess joint space narrowing (JSN). Mixed effects models examined the effect of BMI-depressive symptoms interactions on outcomes of cartilage T2, JSN, and knee pain over 4-years. RESULTS: The BMI-depressive symptoms interaction was significantly associated with knee pain (p < 0.001) changes over 4 years, but not with changes in cartilage T2 (p = 0.27). In women, the BMI-depressive symptoms interaction was significantly associated with JSN (p = 0.01). In a group-based analysis, participants with obesity and depression had significantly greater 4-year changes in knee pain (coeff.(obesity + depression vs. no_obesity + no_depression) = 4.09, 95%CI = 3.60-4.58, p < 0.001), JSN (coeff. = 0.60, 95%CI = 0.44-0.77, p < 0.001), and cartilage T2 (coeff. = 1.09, 95%CI = 0.68-1.49, p < 0.001) than participants without depression and normal BMI. CONCLUSIONS: The compound effects of obesity and depression have greater impact on knee pain and JSN progression compared to what would be expected based on their individual effects.

Good outcome associated with blood-brain barrier disruption and lower blood pressure after endovascular therapy.

OBJECTIVES: To evaluate the association between post-endovascular thrombectomy (EVT) blood-brain barrier (BBB) disruption on MRI or CT and average systolic blood pressure (SBP) with favorable 90-day functional outcome. Observational studies have found elevated SBP associated with worse outcomes post-EVT, while recent randomized trials found no difference in targeted BP reduction. There may be a subgroup of patients who benefit from targeted BP reduction post-EVT. METHODS: This is a single-center study of 1) anterior large vessel occlusion stroke patients treated with EVT from 2015 to 2021, 2) achieved mTICI grade 2b or 3. Hyperintense acute reperfusion marker (HARM), hemorrhagic transformation (HT), and midline shift at 3 h post-EVT and 24 h imaging were assessed independently by multiple raters. Binary logistic regression models were used to determine the association of post-EVT SBP with outcomes. BBB disruption was defined as HT or HARM on 3h post-EVT imaging. RESULTS: Of 103 patients, those with SBP 100-129 versus SBP 130-160 found no significant difference in favorable 90-day outcome (64% vs. 46%, OR 2.11, 95% CI 0.78-5.76, p=0.143). However, among 71 patients with BBB disruption, a significant difference in favorable outcome of 64% in SBP 100-129 vs. 39% in SBP 130-160 group (OR 5.93, 95% CI 1.50-23.45, p=0.011) was found. There was no difference in symptomatic ICH, 90-day mortality, midline shift (≥5 mm), and hemicraniectomy, between BP or BBB groups. CONCLUSIONS: BBB disruption on 3h post-EVT imaging and lower SBP was associated with favorable outcome. This imaging finding may guide targeted BP therapy and suggests need for a randomized control trial.

Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging.

BACKGROUND: Perfusion weighted imaging (PWI) is critical for determining whether stroke patients presenting in an extended time window are candidates for mechanical thrombectomy. However, PWI is not always available. Fluid-attenuated inversion recovery hyperintense vessels (FHVs) are seen in patients with a PWI lesion. We investigated whether a scale measuring the extent FHV could serve as a surrogate for PWI to determine eligibility for thrombectomy. METHODS: The National Institutes of Health (NIH) FHV score was developed to quantify the burden of FHV and applied to magnetic resonance imaging scans of stroke patients with fluid-attenuated inversion recovery and perfusion imaging. The NIH-FHV was combined with the diffusion weighted image volume to estimate the diffusion-perfusion mismatch ratio. Linear regression was used to compare PWI volumes and mismatch ratios with estimates from the NIH-FHV score. Receiver operating characteristic analysis was used to test the ability of the NIH-FHV score to identify a significant mismatch. RESULTS: There were 101 patients included in the analysis, of whom 78% had a perfusion deficit detected on PWI with a mean lesion volume of 47 (±59) mL. The NIH-FHV score was strongly associated with the PWI lesion volume (P<0.001; R2=0.32; ß-coefficient, 0.57). When combined with diffusion weighted image lesion volume, receiver operating characteristic analysis testing the ability to detect a mismatch ratio ≥1.8 using the NIH-FHV score resulted in an area under the curve of 0.94. CONCLUSIONS: The NIH-FHV score provides an estimate of the PWI lesion volume and, when combined with diffusion weighted imaging, may be helpful when trying to determine whether there is a clinically relevant diffusion-perfusion mismatch in situations where perfusion imaging is not available. Further studies are needed to validate this approach.

Variants of Concern Are Overrepresented Among Postvaccination Breakthrough Infections of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Washington State.

Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOCs) and had a median Ct of 20.2 (IQR, 17.1-23.3). When compared with 5174 contemporaneous samples sequenced in our laboratory, VOCs were significantly enriched among breakthrough infections (P < .05).

Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial.

BACKGROUND & AIMS: The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years. METHODS: Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively. RESULTS: Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE. CONCLUSIONS: Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Observed Versus Expected COVID-19 Infections Among National Football League Players During the 2020 Season.

BACKGROUND: The National Football League (NFL) and National Football League Players Association implemented a set of strict protocols for the 2020 season with the intent to mitigate COVID-19 risk among players and staff. In that timeframe, the league's 32 teams completed 256 regular season games and several thousand meetings and practices. In parallel, community cases of COVID-19 were highly prevalent. We assess the risk of holding a 2020 NFL season by comparing community and player COVID-19 infections. METHODS: We used county-level COVID-19 test data from each team to establish baseline distributions of infection rates expected to occur in a population similar in age and sex to NFL players. We used a binomial distribution to simulate expected infections in each community cohort and compared these findings with observed COVID-19 infections in players. RESULTS: Over a 5-month period (1 August 2020 to 2 January 2021), positive NFL player infections (n = 256) were 55.7% lower than expected when compared with simulations from NFL community cohorts. For 30 of 32 teams (94%), observed counts fell at or below expectation, including 28 teams (88%) for which rates were lower. Two teams fell above baseline expectation. CONCLUSIONS: The NFL/NFLPA protocols that governed team facilities, travel, gameday, and activities outside of the workplace were associated with lower infection rates among NFL players compared with the surrounding community. The NFL's 2020-2021 season are consistent with the hypothesis that robust testing and behavioral protocols support a safe return to sport and work.

Association of Multiple Passes during Mechanical Thrombectomy with Incomplete Reperfusion and Lesion Growth.

INTRODUCTION: Despite complete recanalization by mechanical thrombectomy, abnormal perfusion can be detected on MRI obtained post-endovascular therapy (EVT). The presence of residual perfusion abnormalities post-EVT may be associated with blood-brain barrier breakdown in response to mechanical disruption of the endothelium from multiple-pass thrombectomy. We hypothesize that multiple-pass versus single-pass thrombectomy is associated with a higher rate of residual hypoperfusion and increased lesion growth at 24 h. MATERIALS AND METHODS: For this analysis, we included patients presenting to one of two stroke centers between January 2015 and February 2018 with an acute ischemic stroke within 12 h from symptom onset if they had a large vessel occlusion of the anterior circulation documented on magnetic resonance angiography or CTA, baseline MRI pre-EVT with imaging evidence of hypoperfusion, underwent EVT, and had a post-EVT MRI with qualitatively interpretable perfusion-weighted imaging data at 24 h. MRI Tmax maps using a time delay threshold of >6 s were used to quantitate hypoperfusion volumes. Residual hypoperfusion at 24 h was solely defined as Tmax volume >10 mL with >6 s delay. Complete recanalization was defined as modified treatment in cerebral infarction visualized on angiography at EVT completion. Hyperintense acute reperfusion injury marker was assessed on post-EVT pre-contrast fluid-attenuated inversion recovery at 24 h. Major early neurological improvement was defined as a reduction of the admission National Institutes of Health Stroke Scale by ≥8 points or a score of 0-1 at 24 h. Good functional outcome was defined as 0-2 on the modified Rankin Scale on day 30 or 90. RESULTS: Fifty-five patients were included with median age 67 years, 58% female, 45% Black/African American, 36% White/Caucasian, median admission National Institutes of Health Stroke Scale 19, large vessel occlusion locations: 71% M1, 14.5% iICA, 14.5% M2, 69% treated with intravenous recombinant tissue plasminogen activator. Of these, 58% had multiple-pass thrombectomy, 39% had residual perfusion abnormalities at 24 h, and 64% had severe hyperintense acute reperfusion injury marker at 24 h. After adjusting for complete recanalization, only multiple-pass thrombectomy (odds ratio, 4.3 95% CI, 1.07-17.2; p = 0.04) was an independent predictor of residual hypoperfusion at 24 h. Patients with residual hypoperfusion had larger lesion growth on diffusion-weighted imaging (59 mL vs. 8 mL, p < 0.001), lower rate of major early neurological improvement (24% vs. 70%, p = 0.002) at 24 h, and worse long-term outcome based on the modified Rankin Scale at 30 or 90 days, 5 versus 2 (p < 0.001). CONCLUSIONS: Our findings suggest that incomplete reperfusion on post-EVT MRI is present even in some patients with successful recanalization at the time of EVT and is associated with multiple-pass thrombectomy, lesion growth, and worse outcome. Future studies are needed to investigate whether patients with residual hypoperfusion may benefit from immediate adjunctive therapy to limit lesion growth and improve clinical outcome.