Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

cSurvival: a web resource for biomarker interactions in cancer outcomes and in cell lines.

Survival analysis is a technique for identifying prognostic biomarkers and genetic vulnerabilities in cancer studies. Large-scale consortium-based projects have profiled >11 000 adult and >4000 pediatric tumor cases with clinical outcomes and multiomics approaches. This provides a resource for investigating molecular-level cancer etiologies using clinical correlations. Although cancers often arise from multiple genetic vulnerabilities and have deregulated gene sets (GSs), existing survival analysis protocols can report only on individual genes. Additionally, there is no systematic method to connect clinical outcomes with experimental (cell line) data. To address these gaps, we developed cSurvival (https://tau.cmmt.ubc.ca/cSurvival). cSurvival provides a user-adjustable analytical pipeline with a curated, integrated database and offers three main advances: (i) joint analysis with two genomic predictors to identify interacting biomarkers, including new algorithms to identify optimal cutoffs for two continuous predictors; (ii) survival analysis not only at the gene, but also the GS level; and (iii) integration of clinical and experimental cell line studies to generate synergistic biological insights. To demonstrate these advances, we report three case studies. We confirmed findings of autophagy-dependent survival in colorectal cancers and of synergistic negative effects between high expression of SLC7A11 and SLC2A1 on outcomes in several cancers. We further used cSurvival to identify high expression of the Nrf2-antioxidant response element pathway as a main indicator for lung cancer prognosis and for cellular resistance to oxidative stress-inducing drugs. Altogether, these analyses demonstrate cSurvival's ability to support biomarker prognosis and interaction analysis via gene- and GS-level approaches and to integrate clinical and experimental biomedical studies.

Sex differences in cerebral blood flow among adolescents with bipolar disorder.

BACKGROUND: Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. OBJECTIVE: To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). METHODS: CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13-20 years). Whole brain voxel-wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex-diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups). RESULTS: A main effect of diagnosis (BD > HC) was observed in the superior longitudinal fasciculus (SLF), underlying the left precentral gyrus (F =10.24 (3), p < 0.0001). A main effect of sex (F > M) on CBF was detected in the precuneus/posterior cingulate cortex (PCC), left frontal and occipital poles, left thalamus, left SLF, and right inferior longitudinal fasciculus (ILF). No regions demonstrated a significant sex-by-diagnosis interaction. Exploratory pairwise testing in regions with a main effect of sex revealed greater CBF in females with BD versus HC in the precuneus/PCC (F = 7.1 (3), p < 0.01). CONCLUSION: Greater CBF in female adolescents with BD versus HC in the precuneus/PCC may reflect the role of this region in the neurobiological sex differences of adolescent-onset BD. Larger studies targeting underlying mechanisms, such as mitochondrial dysfunction or oxidative stress, are warranted.

Intensive pre-operative information course (IPIC) and pre-operative weight loss results in long-term sustained weight loss following bariatric surgery: 11 years results from a tertiary referral centre.

INTRODUCTION: Outcomes of long-term (5-10-year) weight loss have not been investigated thoroughly and the role of pre-operative weight loss on long-term weight loss, among other factors, are unknown. Our regional bariatric service introduced a 12 week intensive pre-operative information course (IPIC) to optimise pre-operative weight loss and provide education prior to bariatric surgery. The present study determines the effect of pre-operative weight loss and an intense pre-operative information course (IPIC), on long-term weight outcomes and sustained weight loss post-bariatric surgery. METHODS: Data were collected prospectively from a bariatric center (2008-2022). Excess weight loss (EWL) ≥ 50% and ≥ 70% were considered outcome measures. Survival analysis and logistic regression identified variables associated with overall and sustained EWL ≥ 50% and ≥ 70%. RESULTS: Three hundred thirty-nine patients (median age, 49 years; median follow-up, 7 years [0.5-11 years]; median EWL%, 49.6%.) were evaluated, including 158 gastric sleeve and 161 gastric bypass. During follow-up 273 patients (80.5%) and 196 patients (53.1%) achieved EWL ≥ 50% and ≥ 70%, respectively. In multivariate survival analyses, pre-operative weight loss through IPIC, both < 10.5% and > 10.5% EWL, were positively associated with EWL ≥ 50% (HR 2.23, p < 0.001) and EWL ≥ 70% (HR 3.24, p < 0.001), respectively. After a median of 6.5 years after achieving EWL50% or EWL70%, 56.8% (154/271) had sustained EWL50% and 50.6% (85/168) sustained EWL70%. Higher pre-operative weight loss through IPIC increased the likelihood of sustained EWL ≥ 50% (OR, 2.36; p = 0.013) and EWL ≥ 70% (OR, 2.03; p = 0.011) at the end of follow-up. CONCLUSIONS: IPIC and higher pre-operative weight loss improve weight loss post-bariatric surgery and reduce the likelihood of weight regain during long-term follow-up.

High-intensity exercise does not protect against orthostatic intolerance following bedrest in 55- to 65-yr-old men and women.

Prolonged bedrest provokes orthostatic hypotension and intolerance of upright posture. Limited data are available on the cardiovascular responses of older adults to head-up tilt following bedrest, with no studies examining the potential benefits of exercise to mitigate intolerance in this age group. This randomized controlled trial of head-down bedrest (HDBR) in 55- to 65-yr-old men and women investigated if exercise could avert post-HDBR orthostatic intolerance. Twenty-two healthy older adults (11 female) underwent a strict 14-day HDBR and were assigned to either an exercise (EX) or control (CON) group. The exercise intervention included high-intensity, aerobic, and resistance exercises. Head-up tilt-testing to a maximum of 15 minutes was performed at baseline (Pre-Bedrest) and immediately after HDBR (R1), as well as 6 days (R6) and 4 weeks (R4wk) later. At Pre-Bedrest, three participants did not complete the full 15 minutes of tilt. At R1, 18 did not finish, with no difference in tilt end time between CON (422 ± 287 s) and EX (409 ± 346 s). No differences between CON and EX were observed at R6 or R4wk. At R1, just 1 participant self-terminated the test with symptoms, while 12 others reported symptoms only after physiological test termination criteria were reached. Finishers on R1 protected arterial pressure with higher total peripheral resistance relative to Pre-Bedrest. Cerebral blood velocity decreased linearly with reductions in arterial pressure, end-tidal CO2, and cardiac output. High-intensity interval exercise did not benefit post-HDBR orthostatic tolerance in older adults. Multiple factors were associated with the reduction in cerebral blood velocity leading to intolerance.

Laparoscopic Lumen-guided cholecystectomy in face of the difficult gallbladder.

BACKGROUND: Where the critical view of safety cannot be established during cholecystectomy, certain salvage techniques are indicated to reduce the likelihood of bile duct injury. The present study describes a salvage technique termed the "laparoscopic lumen-guided cholecystectomy" (LLC) and reports its peri-operative outcomes. METHOD: A summary of the technique is as follows: (1) Hartmann's pouch is incised and stones are evacuated; (2) the cystic anatomy is inspected from the inside of the gallbladder; (3) the lumen is used to guide retrograde dissection towards the cystic pedicle; (4) cystic duct control is achieved if deemed safe. LLC cases performed between June 2020 and January 2022 in a single health board were included. The operative details and peri-operative outcomes of the technique are reported and compared to cases of similar difficulty where the LLC was not attempted. RESULTS: LLC was performed in 4.6% (27/587) of cases. In all 27 cases, LLC was performed for a "frozen" cholecystohepatic triangle. Hartmann's pouch was completely excised in all cases (27/27) and cystic duct control was achieved in 85.2% of cases (23/27). No cases of bile leak or ductal injury were reported. Rates of bile leak, post-operative complications and ERCP were lower following LLC compared to the group where LLC was not attempted (p < 0.01). CONCLUSION: LLC is a safe salvage technique and should be considered in cases where the critical view of safety cannot be established. The technique achieves cystic duct control in the majority of cases and favourable outcomes in the face of a difficult cholecystectomy.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.

Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.

Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Three waves of COVID-19 in a Norwegian local hospital. / Tre bølger med covid-19 på et norsk lokalsykehus.

BACKGROUND: The objective of this article is to summarise the course of illness and treatment for patients with COVID-19 admitted to Bærum Hospital since the start of the pandemic. MATERIAL AND METHOD: We present data from a prospective observational study with the aim of systematising knowledge about patients admitted because of COVID-19. All patients admitted to Bærum Hospital up to and including 28 June 2021 were included. The results are presented for three waves of admissions: 9 March-23 June 2020, 21 September 2020-28 February 2021 and 1 March-28 June 2021. RESULTS: A total of 300 patients, divided into 77, 101 and 122 in the three waves respectively, were admitted because of COVID-19. The number of hospital deaths during the three waves was 14 (18 %), 11 (11 %) and 5 (4 %) respectively. The average age of the patients was 67.6 years in the first wave and 53.3 years in the third wave. Altogether 204 patients (68 %) received medical oxygen or ventilation support, and 31 of these (10 % of all the patients) received invasive ventilation support. Non-invasive ventilation support was used as the highest level of treatment in 4 (8 %), 9 (13 %) and 17 (20 %) patients with respiratory failure in the three waves respectively. In the second and third wave, 125 out of 152 patients with respiratory failure (82 %) were treated with dexamethasone. INTERPRETATION: Differences in patient characteristics and changes to treatment methods, such as the use of dexamethasone and non-invasive ventilation support, may have contributed to the apparent fall in mortality from the first to the third wave. Conditions that are not registered in the study, such as vaccination status, may also have impacted on mortality.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

225Ac-H4py4pa for Targeted Alpha Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

Emerging synthetic drugs for the treatment of liver cirrhosis.

Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.

Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort.

BACKGROUND AND AIM: Ustekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease. METHODS: We conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein ≥ 5 mg/L or fecal calprotectin ≥ 250 µg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8 weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0 years, interquartile range [IQR] 28.8-51.8 years; disease duration, 9.9 years, IQR 6.0-16.5 years; prior biologic, 98.6%) with a median follow-up of 35.0 weeks (IQR 17.4-52.0 weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n = 37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up. CONCLUSION: Ustekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.

Online Information About the Effectiveness of Shoulder Surgery Is Not Based on the Best Available Evidence: A Content Analysis.

OBJECTIVE: To summarize the proportion of consumer webpages on subacromial decompression and rotator cuff repair surgery that make an accurate portrayal of the evidence for these operations (primary outcome), mention the benefits and harms of surgery, outline alternatives to surgery, and make various surgical recommendations. DESIGN: Content analysis. SETTING: Online consumer information about subacromial decompression and rotator cuff repair surgery. Webpages were identified through (1) Google searches using terms synonymous with "shoulder pain" and "shoulder surgery" and searching "orthopedic surgeon" linked to each Australian capital city and (2) websites of relevant professional associations (eg, Australian Orthopaedic Association). Two reviewers independently identified webpages and extracted data. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Whether the webpage made an accurate portrayal of the evidence for subacromial decompression or rotator cuff repair surgery (primary outcome), mentioned benefits and harms of surgery, outlined alternatives to surgery, and made various surgical recommendations (eg, delay surgery). Outcome data were summarized using counts and percentages. RESULTS: A total of 155 webpages were analyzed (n=89 on subacromial decompression, n=90 on rotator cuff repair, n=24 on both). Only 18% (n=16) and 4% (n=4) of webpages made an accurate portrayal of the evidence for subacromial decompression and rotator cuff repair surgery, respectively. For subacromial decompression and rotator cuff repair, respectively, 85% (n=76) and 80% (n=72) of webpages mentioned benefits, 38% (n=34) and 47% (n=42) mentioned harms, 94% (n=84) and 92% (n=83) provided alternatives to surgery, and 63% (n=56) and 62% (n=56) recommended delayed surgery (the most common recommendation). CONCLUSIONS: Most online information about subacromial decompression and rotator cuff repair surgery does not accurately portray the best available evidence for surgery and may be inadequate to inform patient decision making.

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac-crown-αMSH Peptide.

Targeted alpha-therapy (TAT) has great potential for treating a broad range of late-stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium-225 (225 Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named 'crown', which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225 Ac-crown-αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225 Ac-crown-αMSH showed favorable tumor-to-background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225 Ac-crown-αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.

Cardiac-Related Pulsatility in the Insula Is Directly Associated With Middle Cerebral Artery Pulsatility Index.

BACKGROUND: Arterial stiffness in large arteries is a risk factor for cerebral small vessel disease and neurodegeneration. The challenge of accessing intracranial pulsatility noninvasively is one reason few studies provide empirical insight on the relationship between large artery and tissue pulsatility in the human brain. PURPOSE: To investigate the association between the functional magnetic resonance imaging (fMRI)-derived cardiac-related pulsatility in the insular cortex and the ultrasound-derived pulsatility index in the middle cerebral artery (MCA-PI). STUDY TYPE: Cross-sectional. POPULATION: Younger adults (11; 25 ± 4 years) and older adults with and without cardiovascular risk factors (44; 70 ± 6 years). FIELD STRENGTH/SEQUENCE: T1 -weighted, fluid attenuated inversion recovery, and T2 *-weighted blood oxygenation level-dependent (BOLD) sequences at 3T. ASSESSMENT: MCA-PI and cardiac-related pulsatility were assessed at rest by transcranial Doppler ultrasound and BOLD fMRI, respectively. STATISTICAL TESTS: Multivariate analyses of covariance between MCA-PI and cardiac-related pulsatility. Analysis of variance was used to assess regional differences. RESULTS: MCA-PI was associated with cardiac-related insular pulsatility (P = 0.037), but not whole-brain pulsatility (P = 0.81). Left insular pulsatility was higher than right insular pulsatility (P < 0.01) and was associated with diastolic blood pressure (P = 0.028). DATA CONCLUSION: We show a correlation between ultrasound and fMRI measures of cerebrovascular pulsatility. This association provides insight into the transmission of pulsatile energy from large basal arteries at the Circle of Willis to downstream cerebrovascular beds and has implications for the utility of cardiac-related pulsatility as a potential marker for cerebral small vessel disease. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1454-1462.

232Th-Spallation-Produced 225Ac with Reduced 227Ac Content.

Recent clinical results have demonstrated remarkable treatment responses of late-stage cancer patients when treated with alpha-emitting radionuclides such as actinium-225 (225Ac). The resulting intense global effort to produce greater quantities of 225Ac has triggered a number of emerging technologies to produce this rare, yet important, radionuclide. Accelerator-based methods for increasing global 225Ac production capacity have focused on the high energy (>100 MeV) proton irradiation of thorium, despite the coproduction of the undesirable 227Ac byproduct at 0.1-0.3% of the 225Ac activity. We at TRIUMF have developed a process for the production of a 225Ra/225Ac generator from irradiated thorium that results in an 225Ac product with reduced 227Ac content. 225Ac was separated from irradiated thorium and coproduced radioactive spallation and fission products using a thorium peroxide precipitation method followed by cation exchange and extraction chromatography. Stable and radioactive tracer studies demonstrated the ability of this method to separate Ac from most other elements, providing a directly produced Ac product with measured 227Ac content of (0.15 ± 0.04)%. A second, indirectly produced Ac product with 227Ac content of <7.5 × 10-5% is obtained by repeating the final extraction chromatography step with the 225Ra-containing fraction. The 225Ra-derived 225Ac showed similar or improved quality compared to the initial, directly produced 225Ac product in terms of chemical purity and radiolabeling capability, the latter of which was comparable with other 225Ac sources reported in the literature.