The role of the aryl hydrocarbon receptor (AhR) in modulating intestinal ILC3s to optimise gut pathogen resistance in lupus and benefits of nutritional AhR ligands.

BACKGROUND AND AIMS: Dysbiosis is emerging as a potential trigger of systemic lupus erythematosus (SLE). Group 3 innate lymphoid cells (ILC3s) are recognised as key regulators of intestinal homeostasis. The aryl hydrocarbon receptor (AhR) is critical to intestinal ILC3 development and function. This mechanistic review aimed to investigate whether AhR activation of gut ILC3s facilitates IL-22-mediated antimicrobial peptide (AMP) production to enhance colonisation resistance and ameliorate SLE pathology associated with intestinal dysbiosis. Furthermore, nutritional AhR ligand potential to enhance pathogen resistance was explored. METHODOLOGY: This mechanistic review involved a three-tranche systematic literature search (review, mechanism, intervention) using PubMed with critical appraisal. Data was synthesised into themes and summarised in a narrative analysis. RESULTS: Preclinical mechanistic data indicate that AhR modulation of intestinal ILC3s optimises pathogen resistance via IL-22-derived AMPs. Pre-clinical research is required to validate this mechanism in SLE. Data on systemic immune consequences of AhR modulation in lupus suggest UVB-activated ligands induce aberrant AhR signalling while many dietary ligands exert beneficial effects. Data on xenobiotic-origin ligands is varied, although considerable evidence has demonstrated negative effects on Th17 to Treg balance. Limited human evidence supports the role of nutritional AhR ligands in modulating SLE pathology. Preclinical and clinical data support anti-inflammatory effects of dietary AhR ligands. CONCLUSION: Current evidence is insufficient to fully validate the hypothesis that AhR modulation of intestinal ILC3s can enhance pathogen resistance to ameliorate lupus pathology driven by dysbiosis. However, anti-inflammatory effects of dietary AhR ligands suggest a promising role as a therapeutic intervention for SLE.

Screening for juvenile idiopathic arthritis associated uveitis with laser flare photometry in the pediatric rheumatology office: a prospective observational study.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) Associated Uveitis (JIA-U) remains one of the most serious complications of JIA in children. Historically, pediatric JIA is diagnosed by an Optometrist or Ophthalmologist; however, barriers to scheduling increase wait times that may delay diagnosis and treatment. The purpose of this study was to evaluate laser flare photometry (LFP) use to diagnose JIA-U in the Pediatric Rheumatology clinic for patients with JIA. METHODS: This prospective, observational study assessed pediatric patients diagnosed with JIA without a previous history of uveitis between January 2020 and September 2022. All patients underwent at least one evaluation of both eyes using a Kowa FM-600 laser flare photometer during a routine Rheumatology appointment, as well as a standard slit lamp examination (SLE) by optometry or ophthalmology during routine clinical care. Data collected at patient visits included demographics, JIA characteristics, treatment, LFP readings, and anterior chamber (AC) cell grade score utilizing the SUN grading system. Data were summarized using descriptive analyses and the uveitis false positive rate was calculated. RESULTS: The study cohort included 58 pediatric patients diagnosed with JIA. The mean age was 8.4 years (1.2-16.3 years) at diagnosis and 11.9 (4.8-16.5 years) at enrollment. The mean duration of disease at time of enrollment was 42 months (range; 0-157 months). Participants were predominantly female (n = 43, 74.1%) and white/Caucasian race (n = 37, 63.8%). The most common JIA subtypes included persistent oligoarticular JIA (n = 19, 32.8%), and RF negative polyarticular JIA (n = 12, 20.7%). There were 12 ANA positive patients (20.7%). At enrollment, 16 patients (27.6%) were not on medications, with 20 (34.5%) on methotrexate, 20 (34.5%) on adalimumab, 6 (10.3%) on tocilizumab, and 5 (8.6%) on etanercept. During the study period, no eye exams detected active uveitis based on SLE with a SUN grade over 0. However, of the 135 LFP readings, 131 (97.0%) were normal, yielding a false positive rate of 3% (95% CI: 0.8%, 7.4%). CONCLUSIONS: LFP is a non-invasive tool that can be utilized in the pediatric rheumatology clinic to evaluate for JIA-U. There is a low false positive rate of LFP when compared with standard slit lamp exam.

Inter-Rater Reliability of EyeSpy Mobile for Pediatric Visual Acuity Assessments by Parent Volunteers.

Purpose: To assess the inter-rater test reliability of the EyeSpy Mobile visual acuity smartphone algorithm when administered to children by eye professionals and parent volunteers. Patients and Methods: Visual acuity test-retest results were analyzed for 106 children assigned to one of three different screenings: (1) An eye technician and pediatric ophthalmologist using their typical visual acuity testing method on a M&S computer; (2) An eye technician and pediatric ophthalmologist using EyeSpy Mobile; (3) An eye technician and parent volunteer using EyeSpy Mobile. Results: All three phases demonstrated a strong agreement between the two testers, with mean test-retest equivalency results within 0.05 logMAR (2.5 letters, 90% CI). Whether testing using their typical technique on an M&S computer or using EyeSpy Mobile, eye professionals obtained statistically closer mean test-retest results than parent volunteers by 1 letter, with equivalency results within 0.03 logMAR (1.5 letters, 90% CI). Conversely, the number of retests within 2 vision lines was statistically greater when EyeSpy mobile was used by parents as compared to eye professional's customary technique on the M&S computer. Conclusion: EyeSpy Mobile provides clinically useful visual acuity test-retest results even when used by first-time parent volunteers. Adaptive visual acuity algorithms have the potential to improve reliability, lessen training requirements, and expand the number of vision screening volunteers in community settings.

Investigating the Role of 17ß-Estradiol on the Serotonergic System, Targeting Soy Isoflavones as a Strategy to Reduce Menopausal Depression: A Mechanistic Review.

Low serotonin is one factor implicated in the development of depression. 17ß-estradiol (E2) has been shown to modulate gene expression regulating the neurotransmission of serotonin. Sex hormone levels fluctuate dramatically during the menopausal transition, coinciding with a 14-fold increased risk of depression. This review aimed to examine the effect of soy isoflavones to support decreased and variable E2 levels before and after menopause, linked to an investigation of the pathophysiological mechanisms underlying the protective influence of E2 on the serotonin pathway. The overall aim of this review is to assess the potential of soy isoflavones to reduce depression in middle-aged women. A systematic literature search was performed in three stages. 1,421 papers were screened for relevance to the research aims and objectives. 63 papers were selected based on pre-defined inclusion/exclusion criteria (13 reviews, 24 mechanistic and 26 intervention studies) and critically appraised. Available research supported the hypotheses that E2 increases serotonin synthesis and availability through stimulation of tryptophan hydroxylase-2 (TPH-2) and decreased degradation by monoamine oxidase-A (MAO-A). There was less scientific agreement on the effects of E2 on serotonin transporter (SERT) and serotonin receptors 1 A and 2 A. Studies varied widely on the effectiveness of soy isoflavones in reducing depressive symptoms in (peri)menopausal women. Animal and human studies acknowledge women's increased risk of depression linked to fluctuating E2 rather than absolute levels. However, mechanisms linking E2 variability with depression remain an underrepresented area of research. Study limitations and heterogeneity may contribute to varying results for soy isoflavones and some effects of E2 on the serotonin pathway.

17ß-estradiol increases serotonin synthesis and availability through its effects on tryptophan hydroxylase-2, monoamine oxidase-A, serotonin transporter and serotonin receptors 1A and 2A.Soy isoflavones may ameliorate depressive symptoms around the menopausal transition by replicating the effect of 17ß-estradiol on serotonin.Combining research on the mechanistic pathway of soy isoflavones with the effectiveness of outcomes can enhance clinical decision-making.

Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells.

AIMS: Group 2 innate lymphoid cells (ILC2s) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI. METHODS AND RESULTS: We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5-/- mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-ß (transforming growth factor-ß)-induced cardiac fibroblast Smad signalling. CONCLUSION: This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.

Interprofessional Care in Obstetrics and Gynecology.

Interprofessional care relates to providing care to an individual in an integrated system of professionals who share and shift the care given, depending on the individual and population need. By broadening the scope of care given by health-care workers (HCWs) or shifting tasks through interprofessional care in Obstetrics and Gynecology, more women and their newborns can benefit from safe deliveries, decreased perinatal morbidity and mortality and through screening and early treatment prevent morbidity and mortality secondary to gynecologic diseases.

The first international Delphi consensus statement on Laparoscopic Gastrointestinal surgery.

BACKGROUND: Laparoscopic surgery has almost replaced open surgery in many areas of Gastro-Intestinal (GI) surgery. There is currently no published expert consensus statement on the principles of laparoscopic GI surgery. This may have affected the training of new surgeons. This exercise aimed to achieve an expert consensus on important principles of laparoscopic GI surgery. METHODS: A committee of 38 international experts in laparoscopic GI surgery proposed and voted on 149 statements in two rounds following a strict modified Delphi protocol. RESULTS: A consensus was achieved on 133 statements after two rounds of voting. All experts agreed on tailoring the first port site to the patient, whereas 84.2% advised avoiding the umbilical area for pneumoperitoneum in patients who had a prior midline laparotomy. Moreover, 86.8% agreed on closing all 15 mm ports irrespective of the patient's body mass index. There was a 100% consensus on using cartridges of appropriate height for stapling, checking the doughnuts after using circular staplers, and keeping the vibrating blade of the ultrasonic energy device in view and away from vascular structures. An 84.2% advised avoiding drain insertion through a ≥10 mm port site as it increases the risk of port-site hernia. There was 94.7% consensus on adding laparoscopic retrieval bags to the operating count and ensuring any surgical specimen left inside for later removal is added to the operating count. CONCLUSION: Thirty-eight experts achieved a consensus on 133 statements concerning various aspects of laparoscopic GI Surgery. Increased awareness of these could facilitate training and improve patient outcomes.

Vitamin D deficiency and female infertility: A mechanism review examining the role of vitamin D in ovulatory dysfunction as a symptom of polycystic ovary syndrome.

Around one billion people worldwide are understood to have sub-optimal levels of vitamin D. Polycystic ovary syndrome (PCOS) is reportedly a primary reason for female infertility. The main objective of this research was to understand the mechanistic role of vitamin D in the pathogenesis of female infertility in PCOS, specifically in relation to ovarian follicle development. In addition, the impact of vitamin D deficiency on oxidative stress and hormone production central to folliculogenesis was explored. The efficacy of vitamin D supplementation as an intervention to ameliorate ovulatory dysfunction in individuals with PCOS was evaluated. The systematic search strategy included three stages of search with a critical appraisal of the accepted papers: 1) other review papers; 2) primary mechanistic animal, in vitro and human studies; 3) primary intervention studies. In total, 80 papers were examined in detail and results analysed and evaluated. Mechanistic evidence indicated an association between vitamin D deficiency and impaired ovulatory function. Sub-optimal vitamin D levels were implicated in disrupted reproductive hormone balance, including overproduction of anti-mullerian hormone (AMH); accumulation of pro-inflammatory Advanced Glycation End Products (AGEs) and formation of Reactive Oxygen Species (ROS) in ovarian tissue, leading to abnormal folliculogenesis. Human intervention studies demonstrated the capability of vitamin D supplementation for restoring sufficient serum calcidiol (25(OH)D) levels in deficient individuals. Furthermore, the anti-inflammatory benefit of vitamin D was illustrated in studies examining the impact on oxidative stress. Co-supplementation with calcium was shown to benefit follicle growth; oxidative stress reduced with calcium, omega-3 fatty acid or probiotic co-supplementation.

AAPOS uniform guidelines for instrument-based pediatric vision screen validation 2021.

BACKGROUND: As instrument-based pediatric vision screening technology has evolved, the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) has developed uniform guidelines (2003, updated 2013) to inform the development of devices that can detect specified target levels of amblyopia risk factors (ARFs) and visually significant refractive error. Clinical experience with the established guidelines has revealed an apparent high level of over-referral for non-amblyopic, symmetric astigmatism, prompting the current revision. METHODS: The revised guidelines reflect the expert consensus of the AAPOS Vision Screening and Research Committees. RESULTS: For studies of automated screening devices, AAPOS in 2021 recommends that the gold-standard confirmatory comprehensive examination failure levels include anisometropia >1.25 D and hyperopia >4.0 D. Astigmatism >3.0 D in any meridian and myopia < -3 D should be detected in children <48 months, whereas astigmatism >1.75 D and myopia < -2 D should be detected after 48 months. Any media opacity >1 mm and manifest strabismus of >8Δ should also be identified. Along with performance in detecting ARFs and refractive error, validation studies should also report screening instrument performance with regard to presence or absence of amblyopia. Instrument receiver operating characteristic curves and Bland-Altman analysis are suggested to improve comparability of validation studies. CONCLUSIONS: Examination failure criteria have been simplified and the threshold for symmetric astigmatism raised compared to the 2013 guidelines, whereas the threshold for amblyogenic anisometropia has been decreased. After age 4 years, lower magnitudes of symmetric astigmatism and myopia are also targeted despite a low risk of amblyopia, because they can influence school performance and may warrant consideration of myopia prevention therapy.

Micro-CT yields high image quality in human fetal post-mortem imaging despite maceration.

BACKGROUND: Current clinical post-mortem imaging techniques do not provide sufficiently high-resolution imaging for smaller fetuses after pregnancy loss. Post-mortem micro-CT is a non-invasive technique that can deliver high diagnostic accuracy for these smaller fetuses. The purpose of the study is to identify the main predictors of image quality for human fetal post-mortem micro-CT imaging. METHODS: Human fetuses were imaged using micro-CT following potassium tri-iodide tissue preparation, and axial head and chest views were assessed for image quality on a Likert scale by two blinded radiologists. Simple and multivariable linear regression models were performed with demographic details, iodination, tissue maceration score and imaging parameters as predictor variables. RESULTS: 258 fetuses were assessed, with median weight 41.7 g (2.6-350 g) and mean gestational age 16 weeks (11-24 weeks). A high image quality score (> 6.5) was achieved in 95% of micro-CT studies, higher for the head (median = 9) than chest (median = 8.5) imaging. The strongest negative predictors of image quality were increasing maceration and body weight (p < 0.001), with number of projections being the best positive imaging predictor. CONCLUSIONS: High micro-CT image quality score is achievable following early pregnancy loss despite fetal maceration, particularly in smaller fetuses where conventional autopsy may be particularly challenging. These findings will help establish clinical micro-CT imaging services, addressing the need for less invasive fetal autopsy methods.

Development and Validation of Image-Based Deep Learning Models to Predict Surgical Complexity and Complications in Abdominal Wall Reconstruction.

Importance: Image-based deep learning models (DLMs) have been used in other disciplines, but this method has yet to be used to predict surgical outcomes. Objective: To apply image-based deep learning to predict complexity, defined as need for component separation, and pulmonary and wound complications after abdominal wall reconstruction (AWR). Design, Setting, and Participants: This quality improvement study was performed at an 874-bed hospital and tertiary hernia referral center from September 2019 to January 2020. A prospective database was queried for patients with ventral hernias who underwent open AWR by experienced surgeons and had preoperative computed tomography images containing the entire hernia defect. An 8-layer convolutional neural network was generated to analyze image characteristics. Images were batched into training (approximately 80%) or test sets (approximately 20%) to analyze model output. Test sets were blinded from the convolutional neural network until training was completed. For the surgical complexity model, a separate validation set of computed tomography images was evaluated by a blinded panel of 6 expert AWR surgeons and the surgical complexity DLM. Analysis started February 2020. Exposures: Image-based DLM. Main Outcomes and Measures: The primary outcome was model performance as measured by area under the curve in the receiver operating curve (ROC) calculated for each model; accuracy with accompanying sensitivity and specificity were also calculated. Measures were DLM prediction of surgical complexity using need for component separation techniques as a surrogate and prediction of postoperative surgical site infection and pulmonary failure. The DLM for predicting surgical complexity was compared against the prediction of 6 expert AWR surgeons. Results: A total of 369 patients and 9303 computed tomography images were used. The mean (SD) age of patients was 57.9 (12.6) years, 232 (62.9%) were female, and 323 (87.5%) were White. The surgical complexity DLM performed well (ROC = 0.744; P < .001) and, when compared with surgeon prediction on the validation set, performed better with an accuracy of 81.3% compared with 65.0% (P < .001). Surgical site infection was predicted successfully with an ROC of 0.898 (P < .001). However, the DLM for predicting pulmonary failure was less effective with an ROC of 0.545 (P = .03). Conclusions and Relevance: Image-based DLM using routine, preoperative computed tomography images was successful in predicting surgical complexity and more accurate than expert surgeon judgment. An additional DLM accurately predicted the development of surgical site infection.

Oxygen and Mortality in COVID-19 Pneumonia: A Comparative Analysis of Supplemental Oxygen Policies and Health Outcomes Across 26 Countries.

Introduction: Hypoxia is the main cause of morbidity and mortality in COVID-19. During the COVID-19 pandemic, some countries have reduced access to supplemental oxygen, whereas other nations have maintained and even improved access to supplemental oxygen. We examined whether variation in the nationally determined oxygen guidelines had any association with national mortality rates in COVID-19. Methods: Three independent investigators searched for, identified, and extracted the nationally recommended target oxygen levels for the commencement of oxygen in COVID-19 pneumonia from the 29 worst affected countries. Mortality estimates were calculated from three independent sources. We then applied both parametric (Pearson's R) and non-parametric (Kendall's Tau B) tests of bivariate association to determine the relationship between case fatality rate (CFR) and target SpO2, and also between potential confounders and CFR. Results: Of the 26 nations included, 15 had employed conservative oxygen strategies to manage COVID-19 pneumonia. Of them, Belgium, France, USA, Canada, China, Germany, Mexico, Spain, Sweden, and the UK guidelines advised commencing oxygen when oxygen saturations (SpO2) fell to 91% or less. A statistically significant correlation was found between SpO2 and CFR both parametrically (R = -0.53, P < 0.01) and non-parametrically (-0.474, P < 0.01). Conclusion: Our study highlights the disparity in oxygen provision for COVID-19 patients between the nations analysed. In those nations that pursued a conservative oxygen strategy, there was an association with higher national mortality rates. We discuss the potential reasons for such an association.

A radiologist's perspective of the value of ultrasound-guided fine needle aspiration cytology in the assessment of head and neck lesions.

This viewpoint presents a radiologist's perspective of the value that can be added by close collaboration and teamwork with cytopathologist colleagues to maximise specimen quality, adequacy, and patient outcomes. Various models are discussed and service evolution through teamwork emphasised. The importance of utilising ultrasound guidance for fine needle aspiration in head and neck lesions and critical appraisal of the literature are reviewed.

The Need for Structured Strategies to Improve Stroke Care in a Rural Telestroke Network in Northern New South Wales, Australia: An Observational Study.

Introduction: A telestroke network in Northern New South Wales, Australia has been developed since 2017. We theorized that the telestroke network development would drive a progressive improvement in stroke care metrics over time. Aim: This study aimed to describe changes in acute stroke workflow metrics over time to determine whether they improved with network experience. Methods: We prospectively collected data of patients assessed by telestroke who received multimodal computed tomography (mCT) and were diagnosed with ischemic stroke or transient ischemic attack from January 2017 to July 2019. The period was divided into two phases (phase 1: January 2017 - October 2018 and phase 2: November 2018 - July 2019). We compared median door-to-call, door-to-image, and door-to-decision time between the two phases. Results: We included 433 patients (243 in phase 1 and 190 in phase 2). Each spoke site treated 1.5-5.2 patients per month. There were Door-to-call time (median 39 in phase 1, 35 min in phase 2, p = 0.18), and door-to-decision time (median 81.5 vs. 83 min, p = 0.31) were not improved significantly. Similarly, in the reperfusion therapy subgroup, door-to-call time (median 29 vs. 24.5 min, p = 0.12) and door-to-decision time (median 70.5 vs. 67.5 min, p = 0.75) remained substantially unchanged. Regression analysis showed no association between time in the network and door-to-decision time (coefficient 1.5, p = 0.32). Conclusion: In our telestroke network, acute stroke timing metrics did not improve over time. There is the need for targeted education and training focusing on both stroke reperfusion competencies and the technical aspects of telestroke in areas with limited workforce and high turnover.

Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics.

High blood pressure (BP) presents a significant public health challenge. Recent findings suggest that altered microbiota can exert a hypertensive effect on the host. One of the possible mechanisms involved is the chronic translocation of its components, mainly lipopolysaccharides (LPS) into systemic circulation leading to metabolic endotoxemia. In animal models, LPS has been commonly used to induce endothelial dysfunction and vascular inflammation. In human studies, plasma LPS concentration has been positively correlated with hypertension, however, the mechanistic link has not been fully elucidated. It is hypothesised here that the LPS-induced direct alterations to the vascular endothelium and resulting hypertension are possible targets for probiotic intervention. The methodology of this review involved a systematic search of the literature with critical appraisal of papers. Three tranches of search were performed: 1) existing review papers; 2) primary mechanistic animal, in vitro and human studies; and 3) primary intervention studies. A total of 70 peer-reviewed papers were included across the three tranches and critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies. The extracted information was coded into key themes and summarized in a narrative analysis. Results highlight the role of LPS in the activation of endothelial toll-like receptor 4 (TLR4) initiating a cascade of interrelated signalling pathways including: 1) Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/ Reactive oxygen species (ROS)/ Endothelial nitric oxide synthase (eNOS) pathway leading to endothelial dysfunction; and 2) Mitogen-Activated Protein Kinase (MAPK) and Nuclear factor kappa B (NF-κB) pathways leading to vascular inflammation. Findings from animal intervention studies suggest an improvement in vasorelaxation, vascular inflammation and hypertension following probiotic supplementation, which was mediated by downregulation of LPS-induced pathways. Randomised controlled trials (RCTs) and systematic reviews provided some evidence for the anti-inflammatory effect of probiotics with statistically significant antihypertensive effect in clinical samples and may offer a viable intervention for the management of hypertension.

Consensus Definition of Fetal Growth Restriction in Intrauterine Fetal Death: A Delphi Procedure.

CONTEXT.­: Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborns are heterogeneous. OBJECTIVES.­: To develop a consensus definition for fetal growth restriction retrospectively diagnosed at fetal autopsy in intrauterine fetal death. DESIGN.­: A modified online Delphi survey in an international panel of experts in perinatal pathology, with feedback at group level and exclusion of nonresponders. The survey scoped all possible variables with an open question. Variables suggested by 2 or more experts were scored on a 5-point Likert scale. In subsequent rounds, inclusion of variables and thresholds were determined with a 70% level of agreement. In the final rounds, participants selected the consensus algorithm. RESULTS.­: Fifty-two experts participated in the first round; 88% (46 of 52) completed all rounds. The consensus definition included antenatal clinical diagnosis of fetal growth restriction OR a birth weight lower than third percentile OR at least 5 of 10 contributory variables (risk factors in the clinical antenatal history: birth weight lower than 10th percentile, body weight at time of autopsy lower than 10th percentile, brain weight lower than 10th percentile, foot length lower than 10th percentile, liver weight lower than 10th percentile, placental weight lower than 10th percentile, brain weight to liver weight ratio higher than 4, placental weight to birth weight ratio higher than 90th percentile, histologic or gross features of placental insufficiency/malperfusion). There was no consensus on some aspects, including how to correct for interval between fetal death and delivery. CONCLUSIONS.­: A consensus-based definition of fetal growth restriction in fetal death was determined with utility to improve management and outcomes of subsequent pregnancies.

Global On Line Fellowship in head and neck surgery and oncology.

The International Federation of Head and Neck Oncologic Societies and Memorial Sloan Kettering Cancer Center in New York have partnered to create the Global On Line Fellowship program, a postgraduate fellowship training opportunity for candidates all around the world who are not able to get on-site fellowship training at centers of excellence. This article delineates the successes, challenges, and future goals for the program.

Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET.

ß-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether ß-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not ß-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

Counting Intraepithelial Lymphocytes: A Comparison Between Routine Staining and CD3 Immunohistochemistry.

Counting intraepithelial lymphocytes (IELs) is a key part of the assessment of duodenal biopsies. Immunohistochemistry (IHC) for CD3 can aid identification of lymphocytes in this context, but it is not evident that counts on hematoxylin and eosin (H&E) and CD3 are comparable. This study aimed to compare the IEL counts in duodenal biopsies using H&E stains and CD3 IHC, and to examine the interobserver variability. Thirty-five paired H&E and CD3 sections were reviewed by 6 pathologists who counted the number of IELs per 100 enterocytes. The counts were categorized into groups: normal (<25 lymphocytes), mildly raised (25-40 lymphocytes), and markedly raised (>40 lymphocytes). CD3 IHC was associated with significantly higher IEL counts than H&E. Four cases with normal H&E counts had raised counts with CD3. There was moderate agreement between observers for both H&E and CD3. Lack of concordance between CD3 and H&E IEL counts suggests that counts derived from the 2 methods may not be comparable to each other and should not be considered equivalent. There was no significant improvement in interobserver variability with CD3 IHC.

Implementation of multimodal computed tomography in a telestroke network: Five-year experience.

AIMS: Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre-including noncontrast CT, CT perfusion, and CT angiography-may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. METHODS: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. RESULTS: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. CONCLUSION: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH.