Cerebral Small Vessel Disease and Infarct Growth in Acute Ischemic Stroke Treated with Intravenous Thrombolysis.

We investigated relations between cerebral small vessel disease (cSVD) markers and evolution of the ischemic tissue from ischemic core to final infarct in people with acute ischemic stroke treated with intravenous thrombolysis. Data from the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) were used. Any pre-existing lacunar infarcts and white matter hyperintensities (WMH) were assessed on magnetic resonance (MR) before thrombolytic therapy. Acute ischemic core and final infarct volume were then assessed by two independent radiologists. The relationship among baseline markers of cSVD, acute ischemic core volume, final infarct volume, infarct growth (IG = final infarct - ischemic core), and infarct growth ratio (IGR = final infarct/ischemic core) was then assessed using linear and ordinal regression adjusted for age, sex, onset-to-treatment time, and stroke severity. We included 165 patients, mean (± SD) age 69.5 (± 15.7) years, 74 (45%) males, mean (± SD) ischemic core volume 25.48 (± 42.22) ml, final infarct volume 52.06 (± 72.88) ml, IG 26.58 (± 51.02) ml, IGR 8.23 (± 38.12). Seventy (42%) patients had large vessel occlusion, 20 (12%) acute small subcortical infarct. WMHs were present in 131 (79%) and lacunar infarcts in 61 (37%) patients. Final infarct volumes were 53.8 ml and 45.2 ml (WMHs/no WMHs), p = 0.139, and 24.6 ml and 25.9 ml (lacunar infarcts/no lacunar infarcts), p = 0.842. In linear and ordinal regression analyses, presence of lacunar infarcts was associated with smaller IG (ß = - 0.17; p = 0.024; cOR = 0.52; 95%CI = 0.28-0.96, respectively) and WMHs were associated with smaller IGR (ß = - 0.30; p = 0.004; cOR = 0.27; 95%CI = 0.11-0.69, respectively). In people with acute ischemic stroke treated with intravenous thrombolysis, cSVD features were associated with smaller growth of the acute ischemic area, suggesting less salvageable tissue at time of reperfusion therapy.

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

Comparability between wearable inertial sensors and an electronic walkway for spatiotemporal and relative phase data in young children aged 6-11 years.

BACKGROUND: Approaches to gait analysis are evolving rapidly and now include a wide range of options: from e-patches to video platforms to wearable inertial measurement unit systems. Newer options for gait analysis are generally more inclusive for the assessment of children, more cost effective and easier to administer. However, there is limited data on the comparability of newer systems with more established traditional approaches in young children. RESEARCH QUESTION: To determine comparability between the Physilog®5 wearable inertial sensor and GAITRite® electronic walkway for spatiotemporal (stride length, time and velocity, cadence) and relative phase (double support time, stance, swing, loading, foot flat and push off) data in young children. METHODS: A total 34 typically developing participants (41% female) aged 6-11 years old median age 8.99 years old (interquartile range 2.83) were assessed walking at self-selected speed over the GAITRite® electronic walkway while concurrently wearing shoe-attached Physilog®5 IMU sensors. Level of agreement was analysed by Lin's concordance correlation coefficient (CCC), Bland-Altman plots and 95% limit of agreement. Systematic bias was assessed using 95% confidence interval of the mean difference. RESULTS: Excellent to almost perfect agreement was observed between systems for spatiotemporal metrics: cadence (CCC=0.996), stride length (CCC=0.993), stride time (CCC=0.996), stride velocity (CCC=0.988). The relative phase metrics adjusted for stride velocity showed improved comparability when compared to the unadjusted metrics: swing adjusted (adj) (CCC=0.635); stance adj (CCC: 0.879); loading adj: (CCC=0.626). SIGNIFICANCE: Spatiotemporal metrics are highly compatible across GAITRite® electronic walkway and Physilog®5 IMU systems in young children. Relative phase metrics were somewhat compatible between systems when adjusted for stride velocity.

Evaluation of food security status, psychological well-being, and stress on BMI and diet-related behaviors among a sample of college students.

OBJECTIVES: The purpose of this study was to evaluate food insecurity on body mass index (BMI) and diet-related behaviors among college students and whether psychological well-being (PWB) and stress levels mediate this relationship. STUDY DESIGN: This was a cross-sectional study. METHODS: Data from 1439 students from the American College Health Association National College Health Assessment III (Fall 2020) were used. Food security status was evaluated by the USDA Six-Item Short Form. PWB was measured using the Diener Flourishing Scale. Diet-related behaviors included the average servings of fruits, vegetables, and sugar-sweetened beverages consumed per day. Stress was measured by self-reported levels. Regression model analysis evaluated the influence of food security status, PWB, and stress levels on BMI. PWB and stress were also tested as mediators in the relationship between food insecurity and BMI. RESULTS: Among our sample of college students, 44.54% (n = 641) were food insecure, and 55.46% (n = 798) were food secure. Multiple regression analysis showed that higher food insecurity, older age, full-time enrollment status, and fifth-year student status were positively associated with a higher BMI score (P < 0.05). Results from mediation models revealed that PWB, but not stress, mediated the relationship between food security and BMI among Black/African American students. Regarding diet-related behaviors, high stress levels mediated the relationship between food insecurity and sugar-sweetened beverage intake among students. CONCLUSIONS: Food insecurity appears to influence BMI in college students. This relationship seems to be mediated by disrupted PWB and a higher intake of sugar-sweetened beverages due to stress.

A novel method of determining the active drag profile in swimming via data manipulation of multiple tension force collection methods.

A novel method aimed at evaluating the active drag profile during front-crawl swimming is proposed. Fourteen full trials were conducted with each trial using a stationary load cell set-up and a commercial resistance trainer to record the tension force in a rope, caused by an athlete swimming. Seven different stroke cycles in each experiment were identified for resampling time dependent data into position dependent data. Active drag was then calculated by subtracting resistance trainer force data away from the stationary load cell force data. Mean active drag values across the stroke cycle were calculated for comparison with existing methods, with mean active drag values calculated between 76 and 140 N depending on the trial. Comparing results with established active drag methods, such as the Velocity Perturbation Method (VPM), shows agreement in the magnitude of the mean active drag forces. Repeatability was investigated using one athlete, repeating the load cell set-up experiment, indicating results collected could range by 88 N depending on stroke cycle position. Variation in results is likely due to inconsistencies in swimmer technique and power output, although further investigation is required. The method outlined is proposed as a representation of the active drag profile over a full stroke cycle.

Pharmacokinetic and pharmacodynamic drug display and simulation systems in anesthesia practice.

PURPOSE OF REVIEW: This review explores the use of tools and displays based on pharmacokinetic and pharmacodynamic (PK/PD) modelling of drugs used in anesthesia. The primary focus is on those tools designed to illustrate the interactions between two or more drugs, or classes of drugs, and in particular, their use in a real-time clinical support role. Off-line, educational tools are also explored. RECENT FINDINGS: Despite initial promise and encouraging supporting data, the use of real-time display of PK/PD is not common except in target-controlled infusion (TCI) pumps. SUMMARY: PK/PD simulation is a useful tool for exposition of the relationship between drug dosing and effect. The initial promise of real-time tools has yet to be realized in routine clinical practice.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Follow-up to low-dose fenfluramine for Sunflower syndrome: A non-randomized controlled trial.

AIM: This study reports on the long-term results for an initial cohort of patients with Sunflower syndrome who enrolled in an open-label study of low-dose fenfluramine as well as the short-term results of a second cohort. METHOD: We conducted a single-center, open-label study at the Massachusetts General Hospital. We analyzed the effect of fenfluramine on handwaving seizure frequency at monthly intervals during a 4-month core study period for the second patient cohort, and we evaluated the long-term (>2 years) effect of fenfluramine for the initial patient cohort. RESULTS: Eight of the 10 patients from the second cohort provided analyzable seizure data. These patients experienced a 33% median reduction in seizure frequency during the core study, as compared to the previously reported 79% for the initial cohort (n = 9). Of the seven patients from the first cohort who remain on fenfluramine in the extension study, five continue to experience benefit. Fenfluramine was overall well tolerated with minimal side effects, reduced appetite and fatigue being the primary adverse events, and no evidence of cardiac valvulopathy or pulmonary hypertension. INTERPRETATION: This study suggests fenfluramine can be an effective, durable, and well-tolerated antiseizure medication option for patients with Sunflower syndrome.

Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.

We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.

IWAVE-An adaptive filter approach to phase lock and the dynamic characterization of pseudo-harmonic waves.

We present a novel adaptive filtering approach to the dynamic characterization of waves of varying frequencies and amplitudes embedded in arbitrary noise backgrounds. This method, known as IWAVE (Iterative Wave Action angle Variable Estimator), possesses critical advantages over conventional techniques, making it a useful new tool in the dynamic characterization of a wide range of data containing embedded oscillating signals. After a review of existing techniques, we present the IWAVE algorithm, derive its key characteristics, and provide tests of its performance using simulated and real world data.

Treatment of Aggressive Retinal Astrocytic Hamartoma with Oral Mechanistic Target of Rapamycin Inhibition.

PURPOSE: To describe the clinical course and outcomes of aggressive retinal astrocytic hamartoma (RAH) treated with oral mechanistic target of rapamycin inhibitors (mTORis). DESIGN: A retrospective clinical case series. PARTICIPANTS: Five patients with genetically confirmed tuberous sclerosis complex and visually significant RAH due to tumor growth or exudation. METHODS: In this retrospective clinical case series, a review of electronic medical records was performed to determine baseline and follow-up ophthalmic examination characteristics, along with ancillary imaging findings, in patients receiving off-label treatment with either oral sirolimus or everolimus for symptomatic RAH. MAIN OUTCOME MEASURES: Visual acuity, change in tumor size, degree of exudation, and adverse effects of the mTORis were evaluated. RESULTS: The 5 patients in this series ranged in age from 8 months to 54 years. Four were treated with sirolimus, and 1 received everolimus. In all the cases, the tumor height was stable or decreased after the treatment (median follow-up duration, 39 months; range, 11-73 months). Exudation improved after the treatment in all the cases. In an 8-month-old infant, frequent upper respiratory tract infections prompted the cessation of treatment. In 1 patient, the mTORi was temporarily withheld because of elevated liver enzyme levels. No other significant adverse effects were noted. CONCLUSIONS: Sirolimus and everolimus should be considered in the management of vision-threatening RAH, particularly in the setting of exudative and rapidly growing tumors. Four of the 5 patients in this series tolerated the oral mTORi and continued with the therapy. There were no serious complications.

The P4 study: Subsequent pregnancy maternal physiology after hypertensive and normotensive pregnancies.

OBJECTIVES: Hypertensive disorders of pregnancy are associated with subsequent increased risk of cardiometabolic disease. Adverse cardiometabolic measures are noted soon after hypertensive versus normotensive pregnancy (NP); to what degree these persist into a subsequent pregnancy (SP) is unknown. This study aimed to assess women's physiology early in SP after hypertensive pregnancy (HP: preeclampsia or gestational hypertension) or NP and compare SP to 6 months postpartum findings from the index pregnancy. STUDY DESIGN: Prospective sub-study of the P4 (Postpartum, Physiology, Psychology and Paediatric) observational cohort. Measurements six months after NP versus HP, and the SP at 11-13 weeks gestation. MAIN OUTCOME MEASURES: Blood pressure (BP), blood and urine tests (urine ACR, HOMA-IR, LDL cholesterol), body composition, and contribution of maternal characteristics and inter-pregnancy factors to BP and body fat (FM%) in SP. RESULTS: 49 women (34 NP, 15 HP). In the SP, post-HP women had higher BP (112/70 mmHg HP vs 102/64 mmHg NP; p < .001), with no significant drop from six months postpartum to early SP. On regression analysis, systolic and diastolic BP at 6-months were the major predictors for SP systolic (p < 0.001) and diastolic (p = 0.009) BP respectively in the SP. Longer interpregnancy interval and increased FM% 6-months postpartum were associated with higher SP FM% (p < 0.001). CONCLUSIONS: BP and body fat six months postpartum were similar early in the SP for HP group, and postpartum BP and FM% were major predictors of their corresponding SP measurements. Postpartum/inter-pregnancy intervention programs to improve these cardiometabolic risk markers might help improve women's long-term health and require investigation.

Validation of shoe-worn Gait Up Physilog®5 wearable inertial sensors in adolescents.

BACKGROUND: Gait Up Physilog® wearable inertial sensors are a powerful alternative to traditional laboratory-based gait assessment for children with gait impairment. To build clinician trust in these devices and ultimately facilitate their use outside confined spaces, studies have examined performance of previous versions of Physilog® wearable inertial sensors but predominant focus has been on older adults. Despite their different gait patterns and behavioural/cognitive profiles, there are limited studies in children. RESEARCH QUESTION: To determine whether key spatiotemporal gait parameters (stride length, time and velocity) collected by shoe-worn Physilog®5 sensors in a hallway assessment protocol are a valid method of gait assessment in typically developing adolescents aged 12-15 years. METHODS: A total 30 typically developing participants (50 % female) median age 13.7 (interquartile range 2.34) were assessed in an exploratory study whilst walking at self-selected speed over the GAITRite® electronic walkway, concurrently wearing Physilog®5 sensors. Concurrent validity was analysed by Lin's concordance correlation coefficient (CCC), Bland-Altman plots and 95 % limit of agreement. Systematic bias was assessed using 95 % confidence interval of the mean difference. RESULTS: Mean stride data demonstrated substantial agreement for stride length (CCC = 0.975) and stride velocity (CCC = 0.979) to almost perfect agreement for stride time (CCC > 0.996). Agreement between the technologies for individual stride-to-stride data remained high for stride time (CCC = 0.952); yet reduced for stride length (CCC = 0.868) and stride velocity (CCC = 0.877). Male/female differences in performance of the technology were observed for stride velocity, favouring females. SIGNIFICANCE: Physilog®5 inertial sensors accurately measure walking in adolescents, with stride time the most accurately detected parameter. This demonstrates that wearables can be used by researchers and clinicians working with adolescent groups as an alternative to fixed systems. These findings will ultimately pave the way to using wearables for assessments with children outside of the laboratory environment.

Fenfluramine for seizures associated with Sunflower syndrome.

AIM: To determine the efficacy of fenfluramine on seizure frequency in patients with Sunflower syndrome. Secondary endpoints were changes in electroencephalogram (EEG) characteristics, cognitive functioning, executive functioning, and quality of life. METHOD: In this open-label study, patients underwent a 4-week baseline period, followed by 3 months of treatment. An oral solution of fenfluramine was administered twice daily for 3 months. The dose was titrated up to a maximum dose of 0.7mg/kg/day or 26mg/day. Cardiac safety was monitored by transthoracic echocardiogram and electrocardiogram. EEGs, abbreviated neuropsychological testing, and questionnaires were administered before starting the study medication and again at the end of the treatment period. RESULTS: Ten patients (eight females, two males; mean age 13y 4mo [SD 4y 11mo], range 7-24y) were enrolled in the study. Nine of the 10 patients completed the core study, eight of whom met the primary endpoint. There were no observations of cardiac valvulopathy or pulmonary hypertension during the study. INTERPRETATION: Treatment with low-dose fenfluramine resulted in a clinically significant reduction in seizure frequency, including hand-waving episodes. Fenfluramine may be an effective treatment option for patients with Sunflower syndrome. What this paper adds Nine patients with Sunflower syndrome were treated with fenfluramine. Eight patients were responders, displaying a ≥30% reduction in seizure activity. Six patients experienced a ≥70% reduction in hand-waving episodes. Improvements on electroencephalogram were observed after treatment with fenfluramine. None of the patients developed evidence of cardiac valvulopathy or pulmonary hypertension.