Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness.

AimsTo characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1].Main methodsAdult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S).Key findingsRelative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair.SignificanceOur findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment

AimsTo characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI).MethodsAdult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin.Key findingsCompared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces.SignificanceOur findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI

Clinical obesity services in public hospitals in Australia: a position statement based on expert consensus

We aimed to describe the current state of specialist obesity services for adults with clinically severe obesity in public hospitals in Australia, and to analyse the gap in resources based on expert consensus. We conducted two surveys to collect information about current and required specialist obesity services and resources using open-ended questionnaires. Organizational level data were sought from clinician expert representatives of specialist obesity services across Australia in 2017. Fifteen of 16 representatives of current services in New South Wales (n = 8), Queensland (n = 1), Victoria (n = 2), South Australia (n = 3), and the Australian Capital Territory (n = 1) provided data. The composition of services varied substantially between hospitals, and patient access to services and effective treatments were limited by strict entry criteria (e.g. body mass index 40 kg/m2 or higher with specific complication/s), prolonged wait times, geographical location (major cities only) and out-of-pocket costs. Of these services, 47% had a multidisciplinary team (MDT), 53% had an exercise physiologist/physiotherapist, 53% had a bariatric surgeon and 33% had pharmacotherapy resources. Key gaps included staffing components of the MDT (psychologist, exercise physiologist/physiotherapist) and access to publicly funded weight loss pharmacotherapy and bariatric surgery. There was consensus on the need for significant improvements in staff, physical infrastructure, access to services, education/training in obesity medicine and targeted research funding. Based on the small number of existing, often under-resourced specialist obesity services that are located only in a few major cities, the vast majority of Australians with clinically severe obesity cannot access the specialist evidence based treatments needed.E. Atlantis, N. Kormas, K. Samaras, P. Fahey, P. Sumithran, S. Glastras, G. Wittert, K. Fusco, R. Bishay, T. Markovic, L. Ding, K. Williams, I. Caterson, V. Chikani, P. Dugdale and J. Dixo

Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study

Background Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes. Methods From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy. Results Over a median follow-up of 9.3 (IQR 4.0-16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2-23.2) vs 3.7 (2.7-5.4) months (log-rank 0.15, p<0.01) in the monotherapy group. Multimodal immunotherapy with TACE demonstrated a numerically longer OS compared with ICI monotherapy with a median 35.1 (16.1-Not Evaluable) vs 16.6 (15.7-32.6) months (log-rank 0.41, p=0.12). In the multimodal treatment group, there were three (10%) grade 3 or higher adverse events (AEs) attributed to immunotherapy compared with seven (6.7%) in the matched ICI monotherapy arm. There were no AEs grade 3 or higher attributed to TACE in the multimodal treatment arm. At 3 months following each TACE in the multimodal arm, there was an overall objective response rate of 84%. There were no significant changes in liver functional reserve 1 month following each TACE. Four patients undergoing multimodal treatment were successfully bridged to transplant. Conclusions TACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients

ATS Core Curriculum 2021. Pediatric Pulmonary Medicine: Pulmonary Infections.

The following is a concise review of the Pediatric Pulmonary Medicine Core reviewing pediatric pulmonary infections, diagnostic assays, and imaging techniques presented at the 2021 American Thoracic Society Core Curriculum. Molecular methods have revolutionized microbiology. We highlight the need to collect appropriate samples for detection of specific pathogens or for panels and understand the limitations of the assays. Considerable progress has been made in imaging modalities for detecting pediatric pulmonary infections. Specifically, lung ultrasound and lung magnetic resonance imaging are promising radiation-free diagnostic tools, with results comparable with their radiation-exposing counterparts, for the evaluation and management of pulmonary infections. Clinicians caring for children with pulmonary disease should ensure that patients at risk for nontuberculous mycobacteria disease are identified and receive appropriate nontuberculous mycobacteria screening, monitoring, and treatment. Children with coronavirus disease (COVID-19) typically present with mild symptoms, but some may develop severe disease. Treatment is mainly supportive care, and most patients make a full recovery. Anticipatory guidance and appropriate counseling from pediatricians on social distancing and diagnostic testing remain vital to curbing the pandemic. The pediatric immunocompromised patient is at risk for invasive and opportunistic pulmonary infections. Prompt recognition of predisposing risk factors, combined with knowledge of clinical characteristics of microbial pathogens, can assist in the diagnosis and treatment of specific bacterial, viral, or fungal diseases