2023 EULAR classification criteria for hand osteoarthritis.

OBJECTIVES: The objective of this study is to develop classification criteria for overall hand osteoarthritis (OA), interphalangeal OA and thumb base OA based on self-reported data and radiographic features. METHODS: The classification criteria sets were developed in three phases. In phase 1, we identified criteria that discriminated hand OA from controls. In phase 2, we used a consensus-based decision analysis approach to derive a clinician-based evaluation of the relative importance of the criteria. In phase 3, we refined the scoring system, determined the cut-offs for disease classification and compared the sensitivity and specificity of the European Alliance of Associations for Rheumatology (EULAR) criteria with the 1990 American College of Rheumatology (ACR) criteria. RESULTS: In persons with hand symptoms and no other disease (including psoriasis) or acute injury that can explain the hand symptoms (mandatory criteria), hand OA can be classified based on age, duration of morning stiffness, number of joints with osteophytes and joint space narrowing, and concordance between symptoms and radiographic findings. Using a sum of scores based on each diagnostic element, overall hand OA can be classified if a person achieves 9 or more points on a 0-15 scale. The cut-off for interphalangeal OA and thumb base OA is 8 points. While the EULAR criteria demonstrated better sensitivity than the ACR criteria in the phase 1 data set, the performance of the two criteria sets was similar in two external cohorts. CONCLUSIONS: International experts developed the EULAR criteria to classify overall hand OA, interphalangeal OA and thumb base OA in clinical studies using a rigorous methodology.

Combining multimodal magnetic resonance brain imaging and machine learning to unravel neurocognitive function in non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To study whether multimodal brain MRI comprising permeability and perfusion measures coupled with machine learning can predict neurocognitive function in young patients with SLE without neuropsychiatric manifestations. METHODS: SLE patients and healthy controls (HCs) (≤40 years of age) underwent multimodal structural brain MRI that comprised voxel-based morphometry (VBM), magnetization transfer ratio (MTR) and dynamic contrast-enhanced (DCE) MRI in this cross-sectional study. Neurocognitive function assessed by Automated Neuropsychological Assessment Metrics was reported as the total throughput score (TTS). Olfactory function was assessed. A machine learning-based model (i.e. glmnet) was constructed to predict TTS. RESULTS: Thirty SLE patients and 10 HCs were studied. Both groups had comparable VBM, MTR, olfactory bulb volume (OBV), olfactory function and TTS. While after correction for multiple comparisons the uncorrected increase in the blood-brain barrier (BBB) permeability parameters compared with HCs did not remain evident in SLE patients, DCE-MRI perfusion parameters, notably an increase in right amygdala perfusion, was positively correlated with TTS in SLE patients (r = 0.636, false discovery rate P < 0.05). A machine learning-trained multimodal MRI model comprising alterations of VBM, MTR, OBV and DCE-MRI parameters mainly in the limbic system regions predicted TTS in SLE patients (r = 0.644, P < 0.0005). CONCLUSION: Multimodal brain MRI demonstrated increased right amygdala perfusion that was associated with better neurocognitive performance in young SLE patients without statistically significant BBB leakage and microstructural abnormalities. A machine learning-constructed multimodal model comprising microstructural, perfusion and permeability parameters accurately predicted neurocognitive performance in SLE patients.

A robust evaluation of 49 high-dose-rate prostate brachytherapy treatment plans including all major uncertainties.

BACKGROUND: Uncertainties in radiotherapy cause deviation from the planned dose distribution and may result in delivering a treatment that fails to meet clinical objectives. The impact of uncertainties is unique to the patient anatomy and the needle locations in HDR prostate brachytherapy. Evaluating this impact during treatment planning is not common practice, relying on margins around the target or organs-at-risk to account for uncertainties. PURPOSE: A robust evaluation framework for HDR prostate brachytherapy treatment plans was evaluated on 49 patient plans, measuring the range of possible dosimetric outcomes to the patient due to 14 major uncertainties. METHODS: Patient plans were evaluated for their robustness to uncertainties by simulating probable uncertainty scenarios. Five-thousand probabilistic and 1943 worst-case scenarios per patient were simulated by changing the position and size of structures and length of dwell times from their nominal values. For each uncertainty scenario, the prostate D90 and maximum doses to the urethra, D0.01cc , and rectum, D0.1cc , were calculated. RESULTS: The D90 was an average 1.16 ± 0.51% (mean ± SD) below nominal values for the probabilistic scenarios; the D0.01cc metric was 2.24 ± 0.90% higher; and D0.1cc was greater by 0.48 ± 0.30%. The D0.01cc and D90 metrics were more sensitive to uncertainties than D0.1cc , with a median of 79.0% and 84.9% of probabilistic scenarios passing the constraints, compared to 96.5%. The median pass-rate for scenarios that passed all three metrics simultaneously was 63.4%. CONCLUSIONS: Assessing treatment plan robustness improves plan quality assurance, is achievable in less than 1-min, and identifies treatment plans with poor robustness, allowing re-optimization before delivery.

On the Generalizability of Time-of-Flight Convolutional Neural Networks for Noninvasive Acoustic Measurements.

Bulk wave acoustic time-of-flight (ToF) measurements in pipes and closed containers can be hindered by guided waves with similar arrival times propagating in the container wall, especially when a low excitation frequency is used to mitigate sound attenuation from the material. Convolutional neural networks (CNNs) have emerged as a new paradigm for obtaining accurate ToF in non-destructive evaluation (NDE) and have been demonstrated for such complicated conditions. However, the generalizability of ToF-CNNs has not been investigated. In this work, we analyze the generalizability of the ToF-CNN for broader applications, given limited training data. We first investigate the CNN performance with respect to training dataset size and different training data and test data parameters (container dimensions and material properties). Furthermore, we perform a series of tests to understand the distribution of data parameters that need to be incorporated in training for enhanced model generalizability. This is investigated by training the model on a set of small- and large-container datasets regardless of the test data. We observe that the quantity of data partitioned for training must be of a good representation of the entire sets and sufficient to span through the input space. The result of the network also shows that the learning model with the training data on small containers delivers a sufficiently stable result on different feature interactions compared to the learning model with the training data on large containers. To check the robustness of the model, we tested the trained model to predict the ToF of different sound speed mediums, which shows excellent accuracy. Furthermore, to mimic real experimental scenarios, data are augmented by adding noise. We envision that the proposed approach will extend the applications of CNNs for ToF prediction in a broader range.

Technology-enhanced community forest management in tropical regions: A state of the art.

Tropical forests provide ecosystem services to around 2.7 billion people. Yet they are reaching tipping points due to social, economic, and environmental pressures. Technology is increasingly being leveraged to expand Community Forest Management (CFM) monitoring capabilities and to potentially increase its effectiveness, but a systematic accounting of this is lacking in the scientific literature. This study employed a mixed-methods approach combining a systematic literature review (SLR) with semi-structured interviews of technology-enhanced CFM (tech-CFM) case studies in tropical forests. From the SLR, evaluation criteria were identified and applied to 23 case studies that employed one or more novel technologies, 8 on the African continent, 9 in the Asia Pacific region, 5 in Latin America, and 1 in multiple regions. The results include classifying 22 monitoring technologies, with satellite remote sensing technology being the most common (17 case studies), followed by mobile devices (10 case studies), which are often integrated with geographic information system (8 case studies) analysis and data platforms. These technologies tend to be deployed in packages that augment each technology's capabilities, beyond their individual uses. Nonetheless, they are limited by poor internet coverage in remote regions, impeding the ability to develop real-time integrated monitoring systems. Tech-CFM shows potential for complementing and integrating with national monitoring system when adequate data collection protocols are in place. Practical social-cultural, technical, and project design recommendations are made for the integration of technology into CFM. Finally, a multi-criteria decision-making framework is developed from the literature-based evaluation criteria to assist practitioners in selecting appropriate technology suites.

Analyzing the effectiveness of environmental impact assessment in Paraná, Brazil and California, United States with fuzzy-set qualitative comparative analysis and the analytical hierarchy process.

Environmental impact assessment (EIA) has become one of the most widespread environmental management instruments. Despite this, EIA is routinely criticized for being ineffective at impacting decision-making. This study compared the EIA systems of Paraná, Brazil and California, United States using the effectiveness dimensions from the EIA literature. This study formats the cases into contextual conditions using the fuzzy-set qualitative comparative analysis (fsQCA) to identify the necessary or sufficient conditions that cause effective outcomes. These effectiveness outcomes are then ranked by EIA stakeholders via the analytical hierarchy process (AHP) to identify stakeholder priorities and to improve stakeholder management. The results show that in Paraná stakeholders identified normative effectiveness as the most important dimension, while stakeholders in California identified this dimension as the second-most important following substantive effectiveness. Public participation was found to be a necessary condition for both substantive and normative effectiveness to occur. Early project definition was found to be sufficient for substantive effectiveness and necessary for normative effectiveness, for which stakeholder coordination was a sufficient condition. This suggests that in order for EIA to influence decision-making and foster sustainable development, greater care needs to be taken to actively engage stakeholders in public participation, with clear roles and project design communicated early on, and a clear role for regulatory authority to promote stakeholder coordination for acceptable outcomes. These findings suggest that some effectiveness dimensions are caused by similar conditions, which could help focus stakeholder management efforts and point to new avenues for future EIA effectiveness research.

Survival Benefit of Solid-Organ Transplantation: 10-Year Update.

IMPORTANCE: Transplantation has transformed into a burgeoning field that is rapidly evolving to optimize organ distribution and survival outcomes. The years since 2012 (the last comprehensive study) have seen changes in transplantation, such as advances in immunotherapy and novel indices, that necessitate an updated analysis of survival benefit. DESIGN: Our goal was to determine the survival benefit for solid-organ transplants in the United Network for Organ Sharing (UNOS) database for a three decade period and provide updates on advancements since 2012. Our retrospective analysis examined data containing U.S. patient records from September 1, 1987, to September 1, 2021. RESULTS: We found that 3,430,272 life-years were saved over our transplant period (4.33 life-years saved per patient); kidney-1,998,492 life-years; liver -767,414; heart-435,312; lung-116,625; pancreas-kidney-123,463; pancreas-30,575; intestine-7901. After matching, 3,296,851 life-years were saved. Life-years saved and median survival increased for all organs between 2012 and 2021. Compared to 2012, median survival increased in kidney (from 12.4 to 14.76 years), liver (from 11.6 to 14.59), heart (9.5 to 11.73), lung (5.2 to 5.63), pancreas-kidney (from 14.5 to 16.88), pancreas (from 13.3 to 16.10). When compared to 2012, the percent transplanted increased in kidney, liver, heart, lung, and intestine, while pancreas-kidney and pancreas show decreased percent transplanted. CONCLUSION: Our study underscores the tremendous survival benefits of solid organ transplantation (over 3.4 million life-years saved) and shows improvements since 2012. Our study also highlights areas of transplantation, notably pancreas transplants, that may necessitate reinvigorated attention.

Sociocultural factors associated with detection of autism among culturally and linguistically diverse communities in Australia.

BACKGROUND: The age at which parents or caregivers first develop concerns about their child's development has significant implications on formal diagnosis and intervention. This study aims to determine the sociocultural factors that are associated with the age and type of first concern reported by parents of autistic children among culturally and linguistically diverse (CALD) communities in Australia. We also assessed whether sociocultural factors predict autism traits measured in terms of social affect (SA), restricted and repetitive behaviours (RRB), and calibrated severity scores (CSS). METHODS: This study is a secondary data analysis of the data collected from six Autism Specific Early Learning and Care Centres (ASELCCs) as part of the Autism Co-operative Research Centre (CRC) program between 2015 and 2019. Data analysed in this study included a family history questionnaire with sociodemographic and sociocultural information, parent-reported age and type of first concern, and clinician/researcher administered Autism Diagnostic Observation Schedule - Second Edition (ADOS-2) which includes standardised domain-wise scores of social affect (SA) and restricted and repetitive behaviours (RRB) as well as calibrated severity scores (CSS), a measure of severity of autism. Primary analysis included multivariable linear regression models to examine the predictive influence of sociodemographic and sociocultural factors on the dependant variables of age of concern (AOC) and the autism traits (SA, RRB, and CSS). RESULTS: The mean AOC in the sample was 18.18 months and the most common concerns were speech/language delay, limited social interaction, and hyperactivity/behavioural changes. The multivariable linear regression models showed factors such as increase in age of child, those from a CALD background, annual family income, sibling's autism diagnosis, and developmental concerns to be significantly associated with parental AOC. Additionally, we also found that increase in child's age and CALD status to be significant predictors of autism trait (RRB) and severity measured in terms of the CSS score. Further, females (compared to males) were associated with higher difficulties with social communication and interaction skills. CONCLUSION: Understanding key factors that contribute to early identification of autism can help tailor awareness programs for parents and caregivers, whilst also informing the development of services focused on serving all CALD communities.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Trends in marginal lung allograft survival: Advanced-age donors improve.

INTRODUCTION: Although lung demand continues to outpace supply, 75% of potential donor lungs are discarded without being transplanted in the United States. To identify the discarded cohorts best suited to alleviate the lung shortage and reduce waitlist mortality, we explored changes in survival over time for five marginal donor definitions: age >60 years, smoking history >20 pack-years, PaO2 /FiO2  < 300 mmHg, purulent bronchoscopic secretions, and chest radiograph infiltrates. METHODS: Our retrospective cohort study separated 27 803 lung recipients in the UNOS Database into three 5-year eras by transplant date: 2005-2009, 2010-2014, and 2015-2019. Multivariable Cox proportional hazards regression and Kaplan-Meier analysis with log-rank test were used to compare survival across the eras. RESULTS: Three definitions-low PaO2 /FiO2 , purulent bronchoscopic secretions, and abnormal chest radiographs-did not bear out as truly marginal, demonstrating lack of significantly elevated risk. Advanced donor age demonstrated considerable survival improvement (HR (95% CI): 1.47 (1.26-1.72) in 2005-2009 down to 1.14 (.97-1.35) for 2015-2019), with protective factors being recipients <60 years, moderate recipient BMI, and low Lung Allocation Score (LAS). Donors with smoking history failed to demonstrate any significant improvement (HR (95% CI): 1.09 (1.01-1.17) in 2005-2009 increasing to 1.22 (1.08-1.38) in 2015-2019). CONCLUSIONS: Advanced donor age, previously the most significant risk factor, has improved to near-benchmark levels, demonstrating the possibility for matching older donors to healthier non-elderly recipients in selected circumstances. Low PaO2 /FiO2 , bronchoscopic secretions, and abnormal radiographs demonstrated survival on par with standard donors. Significant donor smoking history, a moderate risk factor, has failed to improve.

Effect of hematocrit, galactose and ascorbic acid on the blood glucose readings of three point-of-care glucometers.

Glucometers are commonly used in a variety of healthcare settings and use in critically ill patients should not be assumed without appropriate tool validation. The study objective was to evaluate the accuracy of three point-of-care glucometers (POCGs) to assess glucose concentration in human blood sample. The POCGs tested included three different instruments and utilized three factors (hematocrit [Hct], galactose and ascorbic acid) in glucose measurements to determine the glucometers' accuracy and compared to the reference laboratory biochemical analyzer (Cobs 8000, Roche, Basal, Switzerland). In this study, the Nova StatStrip glucometer showed no significant variation compared to the laboratory method at high glucose level with various Hct%. ACCU-Chek Inform II overestimated the glucose results at Hct 22% and underestimated at Hct 62%. The Freestyle glucometer showed lower glucose levels compared to the Cobas 8000 at Hct 62%. The ACCU-Check showed significant increase of blood glucose with low Hct% levels when compared to the laboratory method. The Freestyle showed a decreased level of glucose with high Hct 62% interference compared to the Cobas 8000. Galactose interference 100 and 200 mg/dL dramatically affected the accuracy of ACCU-Chek Inform II. Nevertheless, among all three POCGs in this study, the Nova StatStrip showed the most reliable and stable results for glucose level in the presence of interference. Especially, those in critical care units, whereas the Freestyle Precision Pro and ACCU-Chek Inform II were insufficiently accurate for critically ill patients.

Ketamine-precipitated syndrome of inappropriate antidiuretic hormone secretion in a patient with persistent lumbar pain: a case report.

PURPOSE: To report on an unusual case of ketamine-precipitated syndrome of inappropriate antidiuretic hormone secretion (SIADH) in an individual managed by an outpatient pain specialty team. CLINICAL FEATURES: A 78-yr-old male presented to the emergency department with lethargy, malaise, nausea, and abdominal bloating three days following intravenous ketamine infusion for intractable postsurgical lumbar radicular pain with neuropathic features. The patient had a history of resected prostate cancer, hyperlipidemia, chronic kidney disease, and spinal stenosis and the cause of his symptoms was investigated. He was found to be hyponatremic and the treating team excluded reversible surgical and medical causes. A Naranjo score of 7 was calculated, suggesting that the correlation between ketamine and hyponatremia was "likely." Hence, a diagnosis of ketamine-precipitated SIADH was made. The patient was treated with fluid restriction and symptoms were controlled with antiemetics. He returned to baseline function with resolution of the hyponatremia within three days of discharge. CONCLUSION: This case is of clinical importance for providers using ketamine in the field of pain management as the effect of this medication reaction can be profound. Clinicians should develop an awareness that ketamine can potentiate adverse effects such as SIADH and they should monitor, detect, and manage as appropriate.

RéSUMé: OBJECTIF: Nous signalons un cas inhabituel de syndrome de sécrétion inappropriée d'hormones antidiurétiques (SIADH - syndrome of inappropriate antidiuretic hormone secretion) précipité par la kétamine chez une personne prise en charge par une équipe spécialisée en douleur en soins ambulatoires. CARACTéRISTIQUES CLINIQUES: Un homme de 78 ans s'est présenté à l'urgence souffrant de léthargie, de malaise, de nausées et de ballonnements abdominaux trois jours après avoir reçu une perfusion intraveineuse de kétamine pour le traitement d'une douleur radiculaire lombaire postopératoire rebelle avec des caractéristiques neuropathiques. Le patient avait des antécédents de résection de cancer de la prostate, d'hyperlipidémie, d'insuffisance rénale chronique et de sténose du canal rachidien, et la cause de ses symptômes a été évaluée. Il s'est avéré hyponatrémique et l'équipe soignante a exclu les causes chirurgicales et médicales réversibles. Un score Naranjo de 7 a été calculé, suggérant que la corrélation entre la kétamine et l'hyponatrémie était « probable ¼. Par conséquent, un diagnostic de SIADH précipité par la kétamine a été posé. Le patient a été traité par restriction hydrique et les symptômes ont été contrôlés par des antiémétiques. Il est revenu à son fonctionnement de référence avec la résolution de l'hyponatrémie dans les trois jours suivant son congé. CONCLUSION: Ce cas est important d'un point de vue clinique pour les praticiens qui utilisent la kétamine pour la prise en charge de la douleur, car l'effet de cette réaction médicamenteuse peut être profond. Les cliniciens devraient prendre conscience que la kétamine peut augmenter des effets indésirables tels que le SIADH et ils devraient monitorer, dépister et prendre en charge le patient, le cas échéant.

Characteristics, Comorbidities, and Data Gaps for Coronavirus Disease Deaths, Tennessee, USA.

As of March 2021, coronavirus disease (COVID-19) had led to >500,000 deaths in the United States, and the state of Tennessee had the fifth highest number of cases per capita. We reviewed the Tennessee Department of Health COVID-19 surveillance and chart-abstraction data during March 15‒August 15, 2020. Patients who died from COVID-19 were more likely to be older, male, and Black and to have underlying conditions (hereafter comorbidities) than case-patients who survived. We found 30.4% of surviving case-patients and 20.3% of deceased patients had no comorbidity information recorded. Chart-abstraction captured a higher proportion of deceased case-patients with >1 comorbidity (96.3%) compared with standard surveillance deaths (79.0%). Chart-abstraction detected higher rates of each comorbidity except for diabetes, which had similar rates among standard surveillance and chart-abstraction. Investing in public health data collection infrastructure will be beneficial for the COVID-19 pandemic and future disease outbreaks.

Prevalence and risk factors of food insecurity among Libyan migrant families in Australia.

BACKGROUND: The burden of food insecurity remains a public health challenge even in high income countries, such as Australia, and especially among culturally and linguistically diverse (CALD) communities. While research has been undertaken among several migrant communities in Australia, there is a knowledge gap about food security within some ethnic minorities such as migrants from the Middle East and North Africa (MENA). This study aims to determine the prevalence and correlates of food insecurity among Libyan migrant families in Australia. METHODS: A cross-sectional design utilising an online survey and convenience sampling was used to recruit 271 participants, each representing a family, who had migrated from Libya to Australia. Food security was measured using the single-item measure taken from the Australian Health Survey (AHS) and the 18-item measure from the United States Department of Agriculture Household Food Security Survey Module (USDA HFSSM). Multivariable logistic regression was used to identify independent correlates associated with food insecurity. RESULTS: Using the single-item measure, the prevalence of food insecurity was 13.7% whereas when the 18-item questionnaire was used, more than three out of five families (72.3%) reported being food insecure. In the multivariable logistic regression analysis for the single-item measure, those living alone or with others reported higher odds of being food insecure (AOR = 2.55, 95% CI 1.05, 6.21) compared to those living with their spouse, whereas higher annual income (≥AUD 40,000) was associated with lower odds of food insecurity (AOR = 0.30, 95% CI 0.11, 0.84). Higher annual income was also associated with lower odds of food insecurity (AOR = 0.49, 95% CI 0.25, 0.94) on the 18-item measure. On both single and 18-item measures, larger family size (AOR = 1.27, 95% CI 1.07, 1.49 and AOR = 1.21, 95% CI 1.01, 1.47 respectively) was associated with increased odds of food insecurity. CONCLUSION: This study provides evidence that food insecurity amongst Libyan migrants in Australia is a widespread problem and is associated with a number of sociodemographic and socio-economic factors. The findings of this study serve to contribute to the depth and breadth of food security research among vulnerable communities, in this instance Libyan migrant families.

The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat-Wilson Syndrome.

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat-Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

Closing the sepsis gap: an exploration of sepsis presentations at a remote north Australian emergency department.

INTRODUCTION: The objective of this study was to explore the demographic characteristics, disease specifics and outcomes of adult patients with suspected sepsis presenting to a remote Australian emergency department (ED). A retrospective, uninterrupted time series audit of ED patients presenting with suspected sepsis was conducted. A total of 189 remote presentations were reviewed based on the time of clinician identification of sepsis. METHODS: Retrospective cohort analysis was performed for all adult patients with suspected or confirmed sepsis. RESULTS: A majority of patients presenting with sepsis to a remote hospital were Indigenous (61.9%) with a large proportion (34.9%) presenting by ambulance. Median age was 50 years. Indigenous patients (44.7%, 95%CI 34.1-55.9) were more likely to meet the quick Sequential (sepsis-related) Organ Failure Assessment criteria compared to non-Indigenous patients (27.1% 95%CI 16.6-41.0) (p=0.05 95%CI -1.1-34.3) with higher rates of critical care admission (34.2% v 10.4%) (difference 23.8, p=0.003, 95%CI 7.7-37.5). Congruent with previous research, Indigenous status did not confer a difference in sepsis mortality (12.1% v 11.8%, p=0.91). CONCLUSION: Remote Indigenous patients have worse clinical sepsis scores, are more likely to present by ambulance and require skin and soft tissue source control. This cohort has higher lactate values and critical care requirements but similar mortality rates. Improving access to culturally safe medical care could address this disparity.

Neisseria meningitidis Induces Pathology-Associated Cellular and Molecular Changes in Trigeminal Schwann Cells.

Neisseria meningitidis, a common cause of sepsis and bacterial meningitis, infects the meninges and central nervous system (CNS), primarily via paracellular traversal across the blood-brain barrier (BBB) or blood-cerebrospinal fluid barrier. N. meningitidis is often present asymptomatically in the nasopharynx, and the nerves extending between the nasal cavity and the brain constitute an alternative route by which the meningococci may reach the CNS. To date, the cellular mechanisms involved in nerve infection are not fully understood. Peripheral nerve glial cells are phagocytic and are capable of eliminating microorganisms, but some pathogens may be able to overcome this protection mechanism and instead infect the glia, causing cell death or pathology. Here, we show that N. meningitidis readily infects trigeminal Schwann cells (the glial cells of the trigeminal nerve) in vitro in both two-dimensional and three-dimensional cell cultures. Infection of trigeminal Schwann cells may be one mechanism by which N. meningitidis is able to invade the CNS. Infection of the cells led to multinucleation and the appearance of atypical nuclei, with the presence of horseshoe nuclei and the budding of nuclei increasing over time. Using sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics followed by bioinformatics pathway analysis, we showed that N. meningitidis induced protein alterations in the glia that were associated with altered intercellular signaling, cell-cell interactions, and cellular movement. The analysis also suggested that the alterations in protein levels were consistent with changes occurring in cancer. Thus, infection of the trigeminal nerve by N. meningitidis may have ongoing adverse effects on the biology of Schwann cells, which may lead to pathology.

Basic insights into Zika virus infection of neuroglial and brain endothelial cells.

Zika virus (ZIKV) has recently emerged as an important human pathogen due to the strong evidence that it causes disease of the central nervous system, particularly microcephaly and Guillain-Barré syndrome. The pathogenesis of disease, including mechanisms of neuroinvasion, may include both invasion via the blood-brain barrier and via peripheral (including cranial) nerves. Cellular responses to infection are also poorly understood. This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). Readouts included infection kinetics, intracellular virus localization, viral persistence and cytokine responses. Although not as high as in Vero cells, viral titres exceeded 104 plaque-forming units (p.f.u.) ml-1 in the endothelial/neuroglial cell types, except hOECs. Despite these substantial titres, a relatively small proportion of neuroglial cells were primarily infected. Immunolabelling of infected cells revealed localization of the ZIKV envelope and NS3 proteins in the cytoplasm; NS3 staining overlapped with that of dsRNA replication intermediate and the endoplasmic reticulum (ER). Infected OECs and endothelial cells produced high levels of pro-inflammatory chemokines. Nevertheless, ZIKV was also able to establish persistent infection in hOEC and hCMEC/D3 cells. Taken together, these results provide basic insights into ZIKV infection of endothelial and neuroglial cells and will form the basis for further study of ZIKV disease mechanisms.

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.

Hydrogels with Cell Adhesion Peptide-Decorated Channel Walls for Cell Guidance.

A method is reported for making hollow channels within hydrogels decorated with cell-adhesion peptides exclusively at the channel surface. Sacrificial fibers of different diameters are used to introduce channels within poly(ethylene glycol) hydrogels crosslinked with maleimide-thiol chemistry, which are backfilled with a cysteine-containing peptide solution which is conjugated to the lumen with good spatial efficiency. This allows for peptide patterning in only the areas of the hydrogel where they are needed when used as cell-guides, reducing the amount of required peptide 20-fold when compared to bulk functionalization. The power of this approach is highlighted by successfully using these patterned hydrogels without active perfusion to guide fibroblasts and olfactory ensheathing cells-the latter having unique potential in neural repair therapies.