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Background We previously developed and validated a predictive model to help clinicians identify hospitalized adults with coronavirus disease 2019 (COVID-19) who may be ready for discharge given their low risk of adverse events. Whether this algorithm can prompt more timely discharge for stable patients in practice is unknown. Objectives The aim of the study is to estimate the effect of displaying risk scores on length of stay (LOS). Methods We integrated model output into the electronic health record (EHR) at four hospitals in one health system by displaying a green/orange/red score indicating low/moderate/high-risk in a patient list column and a larger COVID-19 summary report visible for each patient. Display of the score was pseudo-randomized 1:1 into intervention and control arms using a patient identifier passed to the model execution code. Intervention effect was assessed by comparing LOS between intervention and control groups. Adverse safety outcomes of death, hospice, and re-presentation were tested separately and as a composite indicator. We tracked adoption and sustained use through daily counts of score displays. Results Enrolling 1,010 patients from May 15, 2020 to December 7, 2020, the trial found no detectable difference in LOS. The intervention had no impact on safety indicators of death, hospice or re-presentation after discharge. The scores were displayed consistently throughout the study period but the study lacks a causally linked process measure of provider actions based on the score. Secondary analysis revealed complex dynamics in LOS temporally, by primary symptom, and hospital location. Conclusion An AI-based COVID-19 risk score displayed passively to clinicians during routine care of hospitalized adults with COVID-19 was safe but had no detectable impact on LOS. Health technology challenges such as insufficient adoption, nonuniform use, and provider trust compounded with temporal factors of the COVID-19 pandemic may have contributed to the null result. Trial registration ClinicalTrials.gov identifier: NCT04570488.

PurposeProvide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment.MethodsClinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting. In those diagnosed with SARS-CoV-2 infection, Mann–Whitney test was used to a assess risk factors for severe disease and mortality.ResultsThree thousand sixty-two patients met study inclusion criteria with 641 patients tested for SARS-COV-2 by RT-PCR or serology. Overall, 64 patients (2.1%) were diagnosed with SARS-CoV-2 infection by either serology, RT-PCR, or documented clinical diagnosis. Comparing matched patients who received chemotherapy (n = 379) with those who received non-cytotoxic therapies (n = 2343) the incidence of SARS-CoV-2 did not differ between treatment groups (weighted risk; 3.5% CT vs 2.7% E/H, P = .523). Twenty-seven patients (0.9%) expired over follow-up, with 10 deaths attributed to SARS-CoV-2 infection. Chemotherapy was not associated with increased risk for death following SARS-CoV-2 infection (weighted risk; 0.7% CT vs 0.1% E/H, P = .246). Advanced disease (stage IV), age, BMI, and Charlson’s Comorbidity Index score were associated with increased mortality following SARS-CoV-2 infection (P ≤ .05).ConclusionBC treatment, including chemotherapy, can be safely administered in the context of enhanced infectious precautions, and should not be withheld particularly when given for curative intent.

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation., Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation.

Background The On–Off, or long flash, full field electroretinogram (ERG) separates retinal responses to flash onset and offset. Depending on degree of dark-adaptation and stimulus strength the On and Off ERG can be shaped by rod and cone photoreceptors and postreceptoral cells, including ON and OFF bipolar cells. Interspecies differences have been shown, with predominantly positive Off-response in humans and other primates and a negative Off-response in rodents and dogs. However, the rod signaling pathways that contribute to these differential responses have not been characterized. In this study, we designed a long flash protocol in the dog that varied in background luminance and stimulus strength allowing for some rod components to be present to better characterize how rod pathways vary from scotopic to mesopic conditions. Results With low background light the rod a-wave remains while the b-wave is significantly reduced resulting in a predominantly negative waveform in mesopic conditions. Through modeling and subtraction of the rod-driven response, we show that rod bipolar cells saturate with dimmer backgrounds than rod photoreceptors, resulting in rod hyperpolarization contributing to a large underlying negativity with mesopic backgrounds. Conclusions Reduction in rod bipolar cell responses in mesopic conditions prior to suppression of rod photoreceptor responses may reflect the changes in signaling pathway of rod-driven responses needed to extend the range of lighting conditions over which the retina functions.

Background Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. Methods We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an alpha-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. Results We now report interim results. The children's mean (+/- SD) age at the time of HSPC gene therapy was 1.9 +/- 0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. Conclusions The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, ; EudraCT number, .)Hematopoietic Gene Therapy for Hurler Syndrome Eight patients with Hurler syndrome who lacked suitable allogeneic donors received autologous hematopoietic stem and progenitor cells transduced ex vivo with an alpha-L-iduronidase-encoding lentiviral vector. This therapy resulted in extensive metabolic correction in peripheral tissues and the central nervous system.

Mucopolysaccharidosis Type I (MPS I) is caused by deficiency of α-L-iduronidase. Short stature and growth deceleration are common in individuals with the attenuated MPS I phenotype. Study objectives were to assess growth in individuals with attenuated MPS I enrolled in The MPS I Registry while untreated and after initiation of enzyme replacement therapy (ERT) with laronidase (recombinant human iduronidase). Individuals in the MPS I Registry with at least one observation for height and assigned attenuated MPS I phenotype as of September 2020 were included. The cohort included 142 males and 153 females 2-18 years of age. Age and sex adjusted standardized height-for-age z-scores during the natural history and ERT-treatment periods were assessed using linear mixed model repeated measures analyses. Growth curves were estimated during both periods and compared to standard growth charts from the Center for Disease Control (CDC). There was a significantly slower decline in height z-scores with age during the ERT-treated period compared to the natural history period. Estimated average height z-scores in the ERT-treatment versus the natural history period at age 10 were -2.4 versus -3.3 in females and -1.4 versus -2.9 in males (females first treated 3 year; males4.1 year). While median height remained below CDC standards during both the natural history and ERT-treated periods for individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores.

Sarcopenia, broadly defined as the age-related decline in skeletal muscle mass, quality, and function, is associated with chronic low-grade inflammation and an increased likelihood of adverse health outcomes. The regulation of skeletal muscle mass with ageing is complex and necessitates a delicate balance between muscle protein synthesis and degradation. The secretion and transfer of cytokines, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), both discretely and within extracellular vesicles, have emerged as important communication channels between tissues. Some of these factors have been implicated in regulating skeletal muscle mass, function, and pathologies and may be perturbed by excessive adiposity. Indeed, adipose tissue participates in a broad spectrum of inter-organ communication and obesity promotes the accumulation of macrophages, cellular senescence, and the production and secretion of pro-inflammatory factors. Pertinently, age-related sarcopenia has been reported to be more prevalent in obesity; however, such effects are confounded by comorbidities and physical activity level. In this review, we provide evidence that adiposity may exacerbate age-related sarcopenia and outline some emerging concepts of adipose-skeletal muscle communication including the secretion and processing of novel myokines and adipokines and the role of extracellular vesicles in mediating inter-tissue cross talk via lncRNAs and miRNAs in the context of sarcopenia, ageing, and obesity. Further research using advances in proteomics, transcriptomics, and techniques to investigate extracellular vesicles, with an emphasis on translational, longitudinal human studies, is required to better understand the physiological significance of these factors, the impact of obesity upon them, and their potential as therapeutic targets in combating muscle wasting.

If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa.The analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan-Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3-16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7-19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity.The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile.• Lysosomal acid lipase deficiency (LAL-D) is a rare, inherited disease in which fatty material (cholesterol and triglycerides) becomes trapped in cells throughout the body, causing organ damage.• Infants can experience a particularly aggressive form of this disease where the functioning of the liver and intestine is impaired, thus leading to an enlarged abdomen and failure to grow and thrive.• If left untreated, LAL-D in infants leads to death, usually by 6 months of age.• This publication reports the results from 2 studies involving 19 infants with rapidly progressive LAL-D; infants received once-weekly intravenous infusions of sebelipase alfa for up to 3 or 5 years, depending on the study.• Results show that with sebelipase alfa treatment, the likelihood of an infant with LAL-D surviving to 12 months of age is 79% and the likelihood of surviving to 5 years of age is 68%.• Throughout both studies, treatment with sebelipase alfa was associated with (1) improvements in growth (weight, length/height, and arm circumference), (2) improvements in liver function, and (3) a decrease in liver and spleen size.• All patients experienced 1 or more adverse events (unwanted side effects), most of which were mild or moderate in severity; no patient stopped receiving treatment because of these events.

New findings What is the central question of the study? Is Vps34 a nutrient-sensitive activator of mTORC1 in human skeletal muscle? What is the main finding and its importance? We show that altering nutrient availability, via protein-carbohydrate feeding, does not increase Vps34 kinase activity in human skeletal muscle. Instead, feeding increased Vps34-mTORC1 co-localization in parallel to increased mTORC1 activity. These findings may have important implications in the understanding nutrient-induced mTORC1 activation in skeletal muscle via interaction with Vps34. Abstract The Class III PI3Kinase, Vps34, has recently been proposed as a nutrient sensor, essential for activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (21 ± 0.5 yrs, 77.7 ± 9.9 kg, 25.9 ± 2.7 kg/m2 , mean ± SD) ingested a PRO-CHO beverage containing 20/44/1 g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1 h and 3 h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean ± SD) - 0.273 ± 0.040, 1 h - 0.348 ± 0.061, Pearson's Coefficient (r)) where it co-localized with mTOR (PRE - 0.312 ± 0.040, 1 h - 0.348 ± 0.069, Pearson's Coefficient (r)). These alterations occurred in parallel to an increase in S6K1 kinase activity (941 ± 466% of PRE at 1 h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.

Obesity has become a world-wide pandemic and is considered a major risk factor for various diseases. Despite this, recent intriguing clinical observations have been made suggesting that being overweight has some advantages. Overweight and some obese patients were reported to have significantly lower all-cause mortality, described as the 'obesity paradox'. This phenomenon resulted in increased research aimed at investigating the influence of adipose tissue on outcomes of various clinical states including critical illness. In this review, we summarise research findings on the effect burn injury and trauma-related critical illness have on adipose tissue and discuss potential mechanisms by which adipose tissue influences outcomes in burn and other critically ill patients. Burn injury and critical illness influence adipose tissue functionally and morphologically, with circulating levels of fat derived hormones, adipokines, altered in patients following injury and/or critical illness. As adipokines regulate a variety of processes including inflammation and metabolism, this disruption in the adipokine axis may explain the obesity paradox phenomenon observed in critically ill patients. We conclude that further research on the influence of individual adipokines on prognosis in burn and critically ill patients and the mechanisms involved is required to increase understanding of their therapeutic potential.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.

The last decade has seen an enormous increase in long non-coding RNA (lncRNA) research within rheumatology. LncRNAs are arbitrarily classed as non-protein encoding RNA transcripts that exceed 200 nucleotides in length. These transcripts have tissue and cell specific patterns of expression and are implicated in a variety of biological processes. Unsurprisingly, numerous lncRNAs are dysregulated in rheumatoid conditions, correlating with disease activity and cited as potential biomarkers and targets for therapeutic intervention. In this chapter, following an introduction into each condition, we discuss the lncRNAs involved in rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus. These inflammatory joint conditions share several inflammatory signalling pathways and therefore not surprisingly many commonly dysregulated lncRNAs are shared across these conditions. In the interest of translational research only those lncRNAs which are strongly conserved have been addressed. The lncRNAs discussed here have diverse roles in regulating inflammation, proliferation, migration, invasion and apoptosis. Understanding the molecular basis of lncRNA function in rheumatology will be crucial in fully determining the inflammatory mechanisms that drive these conditions.

Background Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood–brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder. Results In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes. Conclusions Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous—especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches.

Background Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12–17 year], nine children [6–11 year], and seven infants/early child [1–5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. Results All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p CO increased by 46.6% (p P Conclusion Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704.

Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100μM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25μM HA (11.19±0.39μm) or 25μM EPI (11.01±0.21μm) compared to the vehicle control (VC; 7.61±0.16μm, both P.001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P = .024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences versus control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/β II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC, and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated versus. CTL cells (all P.050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health.

Summary Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials. Funding British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

To identify long noncoding RNAs (lncRNAs) associated with the inflammatory phenotype of synovial fibroblasts from obese patients with osteoarthritis (OA), and to explore the expression and function of these lncRNAs.Synovium was collected from normal-weight patients with hip fracture (non-OA; n = 6) and from normal-weight (n = 8) and obese (n = 8) patients with hip OA. Expression of RNA was determined by RNA-sequencing and quantitative reverse transcription-polymerase chain reaction. Knockdown of lncRNA was performed using LNA-based GapmeRs. Synovial fibroblast cytokine production was measured by enzyme-linked immunosorbent assay.Synovial fibroblasts from obese patients with OA secreted greater levels of interleukin-6 (IL-6) (mean ± SEM 162 ± 21 pg/ml; P0.001) and CXCL8 (262 ± 67 pg/ml; P0.05) compared to fibroblasts from normal-weight patients with OA (IL-6, 51 ± 4 pg/ml; CXCL8, 78 ± 11 pg/ml) or non-OA patients (IL-6, 35 ± 3 pg/ml; CXCL8, 56 ± 6 pg/ml) (n = 6 patients per group). RNA-sequencing revealed that fibroblasts from obese OA patients exhibited an inflammatory transcriptome, with increased expression of proinflammatory messenger RNAs (mRNAs) as compared to that in fibroblasts from normal-weight OA or non-OA patients (2-fold change, P0.05; n = 4 patients per group). A total of 19 lncRNAs were differentially expressed between normal-weight OA and non-OA patient fibroblasts, and a further 19 lncRNAs were differentially expressed in fibroblasts from obese OA patients compared to normal-weight OA patients (2-fold change, P0.05 for each), which included the lncRNA for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1 was rapidly induced upon stimulation of OA synovial fibroblasts with proinflammatory cytokines, and was up-regulated in the synovium from obese OA patients as compared to normal-weight OA patients (1.6-fold change, P0.001) or non-OA patients (6-fold change, P0.001). MALAT1 knockdown in OA synovial fibroblasts (n = 4 patients) decreased the levels of mRNA expression and protein secretion of CXCL8 (1.5-fold change, P0.01), whereas it increased expression of mRNAs for TRIM6 (2-fold change, P0.01), IL7R (2-fold change, P0.01), HIST1H1C (1.5-fold change, P0.001), and MAML3 (1.5-fold change, P0.001). In addition, MALAT1 knockdown inhibited the proliferation of synovial fibroblasts from obese patients with OA.Synovial fibroblasts from obese patients with hip OA exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients.

Background Despite it being known that subchondral bone affects the viscoelasticity of cartilage, there has been little research into the mechanical properties of osteochondral tissue as a whole system. This study aims to unearth new knowledge concerning the dynamic behaviour of human subchondral bone and how energy is transferred through the cartilage-bone interface. Methods Dynamic mechanical analysis was used to determine the frequency-dependent (1–90 Hz) viscoelastic properties of the osteochondral unit (cartilage-bone system) as well as isolated cartilage and bone specimens extracted from human femoral heads obtained from patients undergoing total hip replacement surgery, with a mean age of 78 years (N = 5, n = 22). Bone mineral density (BMD) was also determined for samples using micro-computed tomography as a marker of tissue health. Results Cartilage storage and loss moduli along with bone storage modulus were found to increase logarithmically (p p − 1, while the loss stiffness was determined to be frequency-independent at 78.84 ± 2.48 N.mm− 1. Notably, a statistically significant (p p = 0.09). Conclusions The viscoelastic properties of the cartilage-bone core were significantly different to the tissues in isolation (p

Study Design An observational descriptive study based on a single cohort of patients. Objective To determine whether spinal facet osteoblasts at the curve apex display a different phenotype to osteoblasts from outside the curve in adolescent idiopathic scoliosis (AIS) patients. Summary of Background Data Intrinsic differences in the phenotype of spinal facet bone tissue and in spinal osteoblasts have been implicated in the pathology of AIS. However, no study has compared the phenotype of facet osteoblasts at the curve apex compared with outside the curve in AIS patients. Methods Facet spinal tissue was collected perioperatively from three sites, the concave and convex side at the curve apex and from outside the curve (noncurve) from three AIS female patients aged 13–16 years. Spinal tissue was analyzed by micro–computed tomography to determine bone mineral density (BMD) and trabecular structure. Primary osteoblasts were cultured from concave, convex, and noncurve facet bone chips. The phenotype of osteoblasts was determined by assessment of cellular proliferation, cellular metabolism (alkaline phosphatase and Seahorse Analyzer), bone nodule mineralization (Alizarin red assay), and the mRNA expression of Wnt signaling genes (quantitative reverse transcriptase polymerase chain reaction). Results Convex facet tissue exhibited greater BMD and trabecular thickness, compared with concave facet tissue. Osteoblasts at the convex side of the curve apex exhibited a significantly higher proliferative and metabolic phenotype and a greater capacity to form mineralized bone nodules, compared with concave osteoblasts. mRNA expression of SKP2 was significantly greater in both concave and convex osteoblasts, compared with noncurve osteoblasts. The expression of SFRP1 was significantly downregulated in convex osteoblasts, compared with either concave or noncurve. Conclusions Intrinsic differences that affect osteoblast function are exhibited by spinal facet osteoblasts at the curve apex in AIS patients. Level of Evidence Level IV, Prognostic.

Introduction Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA. Methods Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. Results A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). Conclusion This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps. Electronic supplementary material The online version of this article (10.1186/s13023-019-1074-9) contains supplementary material, which is available to authorized users.

Western diet (WD), high in sugar and fat, promotes obesity and associated chronic low-grade pro-inflammatory environment, leading to impaired immune function, reprogramming of innate and adaptive immune cells, and development of chronic degenerative diseases, including cardiovascular disease. Increased concentrations of circulating and tissue ceramides contribute to inflammation and cellular dysfunction common in immune metabolic and cardiometabolic disease. Therefore, ceramide-lowering interventions have been considered as strategies to improve adipose tissue health. Here, we report the ability of omega-3 polyunsaturated fatty acids (n-3PUFA) to attenuate inflammatory phenotypes promoted by WD, through ceramide-dependent pathways. Using an animal model, we show that enrichment of WD diet with n-3PUFA, reduced the expression of ceramide synthase 2 (CerS2), and lowered the concentration of long-chain ceramides (C23-C26) in plasma and adipose tissues. N-3PUFA also increased prevalence of the anti-inflammatory CD4

The identification of elevated IL-6 levels in patients with severe COVID-19 led to the rapid development of clinical trials targeting this cytokine. Overall, these trials do not support the widespread use of IL-6 antagonists in hospitalized patients with mild-to-moderate disease, but IL-6 antagonists may be beneficial when rapidly deployed in patients with severe COVID-19, as we discuss here.

Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA.

The classification of interleukin-6 (IL-6) as a pro-inflammatory cytokine undervalues the biological impact of this cytokine in health and disease. With broad activities affecting the immune system, tissue homeostasis and metabolic processes, IL-6 displays complex biology. The significance of these involvements has become increasingly important in clinical settings where IL-6 is identified as a prominent target for therapy. Here, clinical experience with IL-6 antagonists emphasises the need to understand the context-dependent properties of IL-6 within an inflammatory environment and the anticipated or unexpected consequences of IL-6 blockade. In this review, we will describe the immunobiology of IL-6 and explore the gamut of IL-6 bioactivity affecting the clinical response to biological drugs targeting this cytokine pathway.

Metastasis Associated Lung Adenocarcinoma Transcript-1 (MALAT1) is implicated in regulating the inflammatory response and in the pathology of several chronic inflammatory diseases, including osteoarthritis (OA). The purpose of this study was to examine the relationship between OA subchondral bone expression of MALAT1 with parameters of joint health and biomarkers of joint inflammation, and to determine its functional role in human OA osteoblasts. Subchondral bone and blood were collected from hip and knee OA patients (n = 17) and bone only from neck of femur fracture patients (n = 6) undergoing joint replacement surgery. Cytokines were determined by multiplex assays and ELISA, and gene expression by qPCR. MALAT1 loss of function was performed in OA patient osteoblasts using locked nucleic acids. The osteoblast transcriptome was analysed by RNASeq and pathway analysis. Bone expression of MALAT1 positively correlated to serum DKK1 and galectin-1 concentrations, and in OA patient osteoblasts was induced in response to IL-1β stimulation. Osteoblasts depleted of MALAT1 exhibited differential expression (&gt, 1.5 fold change) of 155 genes, including PTGS2. Both basal and IL-1β-mediated PGE2 secretion was greater in MALAT1 depleted osteoblasts. The induction of MALAT1 in human OA osteoblasts upon inflammatory challenge and its modulation of PGE2 production suggests that MALAT1 may play a role in regulating inflammation in OA subchondral bone.

Obesity is considered a global epidemic developed in part as a consequence of the overconsumption of high fat diets. One of the main negative outcomes of obesity is the development of low-grade chronic systemic inflammation, induced by dysregulated immune responses, which can lead to multiple obesity-related diseases. Ceramides are a group of bioactive lipids known to be elevated in obesity and obesity-associated conditions, including cardiovascular disease and type II diabetes. Ceramides may be key players in promoting an obesity–induced inflammatory environment due to their ability to activate key pathways such as Toll-like receptor 4 (TLR4) and NLR pyrin domain containing receptor 3 (Nlrp3), while studies have shown that inhibition of ceramide synthesis gives rise to an anti-inflammatory environment. N-3 polyunsaturated fatty acids (n-3 PUFA) have been of interest due to their anti-inflammatory actions and shown to have beneficial effects in obesity-related diseases. This review will highlight the impact of ceramides in promoting an obesity-induced inflammatory microenvironment and discuss how n-3 PUFA could potentially counteract these responses and have a regulatory effect promoting immune homeostasis.

Stromal fibroblasts are central mediators of chronic inflammatory disease. Changes to fibroblast metabolism (including glycolysis, oxidative phosphorylation, pentose phosphate pathway, glutamine metabolism and lactate transport) fuels and underpins the switch in fibroblast phenotype towards an inflammatory‐activated phenotype that drives chronic inflammation. Cancer‐associated fibroblasts drive tumour progression, activated synoviocytes drive joint inflammation, and activated myoblasts drive fibrotic disorders including chronic kidney disease, pulmonary fibrosis, heart disease and liver disease., Mesenchymal stromal fibroblasts have emerged as key mediators of the inflammatory response and drivers of localised inflammation, in part through their interactions with resident and circulating immune cells at inflammatory sites. As such, they have been implicated in a number of chronic inflammatory conditions as well as in tumour progression through modifying the microenvironment. The connection between metabolic changes and altered phenotype of fibroblasts in inflammatory microenvironments has clear implications for our understanding of how chronic inflammation is regulated and for the development of new anti‐inflammatory therapeutics. In this review, we consider the evidence that changes to fibroblast metabolic state underpin chronic inflammation. We examine recent research on fibroblast metabolism in inflammatory microenvironments and consider their involvement in inflammation, providing insight into the role of fibroblasts and metabolism in mediating inflammatory disease progression namely cancer, arthritis and fibrotic disorders including chronic kidney disease, pulmonary fibrosis, heart disease and liver disease.

Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal of T-cell dysfunction in CLL may be beneficial to reduce tumor burden. Previous studies have also highlighted roles for histone deacetylase 6 (HDAC6) in regulation of immune cell phenotype and function. Here, we report for the first time that HDAC6 inhibition exerts beneficial immunomodulatory effects on CLL B cells and alleviates CLL-induced immunosuppression of CLL T cells. In the Eμ-TCL1 adoptive transfer murine model, genetic silencing or inhibition of HDAC6 reduced surface expression of programmed death-ligand 1 (PD-L1) on CLL B cells and lowered interleukin-10 (IL-10) levels. This occurred concurrently with a bolstered T-cell phenotype, demonstrated by alteration of coinhibitory molecules and activation status. Analysis of mice with similar tumor burden indicated that the majority of T-cell changes elicited by silencing or inhibition of HDAC6 in vivo are likely secondary to decrease of tumor burden and immunomodulation of CLL B cells. The data reported here suggest that CLL B cell phenotype may be altered by HDAC6-mediated hyperacetylation of the chaperone heat shock protein 90 (HSP90) and subsequent inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Based on the beneficial immunomodulatory activity of HDAC6 inhibition, we rationalized that HDAC6 inhibitors could enhance immune checkpoint blockade in CLL. Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the Eμ-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8+ T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients.

Obesity is associated with chronic low-grade inflammation that affects the phenotype of multiple tissues and therefore is implicated in the development and progression of several age-related chronic inflammatory disorders. Importantly, a new family of noncoding RNAs, termed long noncoding RNAs (lncRNAs), have been identified as key regulators of inflammatory signalling pathways that can mediate both pretranscriptional and posttranscriptional gene regulation. Furthermore, several lncRNAs have been identified, which are differentially expressed in multiple tissue types in individuals who are obese or in preclinical models of obesity. In this review, we examine the evidence for the role of several of the most well-studied lncRNAs in the regulation of inflammatory pathways associated with obesity. We highlight the evidence for their differential expression in the obese state and in age-related conditions including insulin resistance, type 2 diabetes (T2D), sarcopenia, osteoarthritis and rheumatoid arthritis, where obesity plays a significant role. Determining the expression and functional role of lncRNAs in mediating obesity-associated chronic inflammation will advance our understanding of the epigenetic regulatory pathways that underlie age-related inflammatory diseases and may also ultimately identify new targets for therapeutic intervention.

Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood–brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

Emerging studies increasingly demonstrate the importance of the throat and salivary glands as sites of virus replication and transmission in early COVID-19 disease. SARS-CoV-2 is an enveloped virus, characterized by an outer lipid membrane derived from the host cell from which it buds. While it is highly sensitive to agents that disrupt lipid biomembranes, there has been no discussion about the potential role of oral rinsing in preventing transmission. Here, we review known mechanisms of viral lipid membrane disruption by widely available dental mouthwash components that include ethanol, chlorhexidine, cetylpyridinium chloride, hydrogen peroxide, and povidone-iodine. We also assess existing formulations for their potential ability to disrupt the SARS-CoV-2 lipid envelope, based on their concentrations of these agents, and conclude that several deserve clinical evaluation. We highlight that already published research on other enveloped viruses, including coronaviruses, directly supports the idea that oral rinsing should be considered as a potential way to reduce transmission of SARS-CoV-2. Research to test this could include evaluating existing or specifically tailored new formulations in well-designed viral inactivation assays, then in clinical trials. Population-based interventions could be undertaken with available mouthwashes, with active monitoring of outcome to determine efficacy. This is an under-researched area of major clinical need.

Background Therapies targeting anti-tumor T-cell responses have proven successful in the treatment of a variety of malignancies. However, as most patients still fail to respond, approaches to augment immunotherapeutic efficacy are needed. Here, we investigated the ability of histone deacetylase 6 (HDAC6)-selective inhibitors to decrease immunosuppression and enhance immune function of melanoma patient T-cells in ex vivo cultures. Methods T-cells were harvested from peripheral blood or tumor biopsies of metastatic melanoma patients and cultured in the presence of pan-, class-specific or class-selective histone deacetylase (HDAC) inhibitors. Changes in cytokine production were evaluated by Luminex and intracellular flow cytometry staining. Expression of surface markers, transcription factors, protein phosphorylation, and cell viability were assessed by flow cytometry. Changes in chromatin structure were determined by ATAC-seq. Results T-cell viability was impaired with low doses of pan-HDAC inhibitors but not with specific or selective HDAC inhibitors. The HDAC6-selective inhibitors ACY-1215 (ricolinostat) and ACY-241 (citarinostat) decreased Th2 cytokine production (i.e. IL-4, IL-5, IL-6, IL-10 and IL-13). Expansion of peripheral blood T-cells from melanoma patients in the presence of these inhibitors resulted in downregulation of the Th2 transcription factor GATA3, upregulation of the Th1 transcription factor T-BET, accumulation of central memory phenotype T-cells (CD45RA-CD45RO + CD62L + CCR7+), reduced exhaustion-associated phenotypes (i.e. TIM3 + LAG3 + PD1+ and EOMES+PD1+), and enhanced killing in mixed lymphocyte reactions. The frequency, FOXP3 expression, and suppressive function of T regulatory cells (Tregs) were decreased after exposure to ACY-1215 or ACY-241. Higher frequencies of T-cells expressing CD107a + IFNγ+ and central memory markers were observed in melanoma tumor-infiltrating lymphocytes (TIL), which persisted after drug removal and further expansion. After ACY-1215 treatment, increased chromatin accessibility was observed in regions associated with T-cell effector function and memory phenotypes, while condensed chromatin was found in regions encoding the mTOR downstream molecules AKT, SGK1 and S6K. Decreased phosphorylation of these proteins was observed in ACY-1215 and ACY-241-treated T-cells. AKT- and SGK1-specific inhibition recapitulated the increase in central memory frequency and decrease in IL-4 production, respectively, similar to the observed effects of HDAC6-selective inhibition. Conclusions HDAC6-selective inhibitors augmented melanoma patient T-cell immune properties, providing a rationale for translational investigation assessing their potential clinical efficacy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0517-0) contains supplementary material, which is available to authorized users.

Research into hallucinations typically regards them as single sensory or unimodal experiences leading to a comparative neglect of co-occurring multi-sensory hallucinations (MSH). People with psychosis who have visual hallucinations (VH) report high rates of hallucinations in other senses (auditory, olfactory, tactile). However, it is not known if this is similar to other groups who report VH. Consequently, this study explored MSH in four different patient groups who all had current VH. Archival data from standardised assessments of visual hallucinations in people with psychosis (n = 22), eye disease (ED) (n = 82), Lewy body Dementia (LBD) (n = 41), and Parkinson's disease (PD) (n = 41) determined the presence of MSH. People with psychosis and visual hallucinations reported significantly higher rates of MSH (auditory, 73%; tactile, 82%; olfactory/gustatory hallucinations, 27%) than the LBD group (auditory, 21%; tactile, 28%; olfactory/gustatory, 6%), ED (auditory, 1%; tactile, 11%; olfactory/gustatory, 0%) and PD patients (auditory, 3%; tactile, 8%; olfactory/gustatory, 3%). Regardless of diagnostic grouping, participants with MSH reported greater conviction that the VH were real, and reported greater distress. People with psychosis with VH report high rates of MSH unlike groups of older adults with VH. These between group differences in MSH prevalence have implications for clinical practice and theory.

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition.

Changes in cellular metabolism have been implicated in mediating the activated fibroblast phenotype in a number of chronic inflammatory disorders, including pulmonary fibrosis, renal disease and rheumatoid arthritis. The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight hip OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity. Synovium and synovial fluid was obtained from hip OA patients, who were either of normal-weight or obese and were undergoing elective joint replacement surgery. The synovial fluid metabolome was determined by 1H NMR spectroscopy. The metabolic profile of isolated synovial fibroblasts in vitro was characterised by lactate secretion, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF Analyser. The effects of a small molecule pharmacological inhibitor and siRNA targeted at glutaminase-1 (GLS1) were assessed to probe the role of glutamine metabolism in OA synovial fibroblast function. Obese OA patient synovial fluid (n = 5) exhibited a different metabotype, compared to normal-weight patient fluid (n = 6), with significantly increased levels of 1, 3-dimethylurate, N-Nitrosodimethylamine, succinate, tyrosine, pyruvate, glucose, glycine and lactate, and enrichment of the glutamine–glutamate metabolic pathway, which correlated with increasing adiposity. In vitro, isolated obese OA fibroblasts exhibited greater basal lactate secretion and aerobic glycolysis, and increased mitochondrial respiration when stimulated with pro-inflammatory cytokine TNFα, compared to fibroblasts from normal-weight patients. Inhibition of GLS1 attenuated the TNFα-induced expression and secretion of IL-6 in OA synovial fibroblasts. These findings suggest that altered cellular metabolism underpins the inflammatory phenotype of OA fibroblasts, and that targeted inhibition of glutamine–glutamate metabolism may provide a route to reducing the pathological effects of joint inflammation in OA patients who are obese.

Hallucinations can occur in single or multiple sensory modalities. Historically, greater attention has been paid to single sensory modality experiences with a comparative neglect of hallucinations that occur across two or more sensory modalities (multi-modal hallucinations). With growing evidence suggesting that visual hallucinations may be experienced along with other hallucinations, this study aimed to explore multi-modal hallucinations in a sample of people with psychotic disorders who reported visual hallucinations (n = 22). No participants reported just visual hallucinations i.e. all reported related or unrelated auditory hallucinations. Twenty-one participants reported multi-modal hallucinations that were serial in nature, whereby they saw visual hallucinations and heard unrelated auditory hallucinations at other times. Nineteen people out of the twenty two also reported simultaneous multi-modal hallucinations, with the most common being an image that talked to and touched them. Multi-modal related and simultaneous hallucinations appeared to be associated with greater conviction that the experiences were real, and greater distress. Theoretical and clinical implications of multi-modal hallucinations are discussed.

Hallucinations are a characteristic symptom of psychotic mental health conditions that are also experienced by many individuals without a clinical diagnosis. Hallucinations in schizophrenia have been linked to differences in the length of the paracingulate sulcus (PCS), a structure in the medial prefrontal cortex which has previously been associated with the ability to differentiate perceived and imagined information. We investigated whether this putative morphological basis for hallucinations extends to individuals without a clinical diagnosis, by examining whether nonclinical individuals with hallucinations have shorter PCS than nonclinical individuals without hallucinations. Structural MRI scans were examined from 3 demographically matched groups of individuals: 50 patients with psychotic diagnoses who experienced auditory verbal hallucinations (AVHs), 50 nonclinical individuals with AVHs, and 50 healthy control subjects with no life-time history of hallucinations. Results were verified using automated data-driven gyrification analyses. Patients with hallucinations had shorter PCS than both healthy controls and nonclinical individuals with hallucinations, with no difference between nonclinical individuals with hallucinations and healthy controls. These findings suggest that the association of shorter PCS length with hallucinations is specific to patients with a psychotic disorder. This presents challenges for full-continuum models of psychosis and suggests possible differences in the mechanisms underlying hallucinations in clinical and nonclinical groups.

Articular cartilage is a viscoelastic tissue whose structural integrity is important in maintaining joint health. To restore the functionality of osteoarthritic joints it is vital that regenerative strategies mimic the dynamic loading response of cartilage and bone. Here, a rotating simplex model was employed to optimise the composition of agarose and gellan hydrogel constructs structured with hydroxyapatite (HA) with the aim of obtaining composites mechanically comparable to human cartilage in terms of their ability to dissipate energy. Addition of ceramic particles was found to reinforce both matrices up to a critical concentration (< 3w/v%). Beyond this, larger agglomerates were formed, as evidenced by micro computed tomography data, which acted as stress risers and reduced the ability of composites to dissipate energy demonstrated by a reduction in tan δ values. A maximum compressive modulus of 450.7±24.9 kPa was achieved with a composition of 5.8w/v% agarose and 0.5w/v% HA. Interestingly, when loaded dynamically (1-20Hz) this optimised formulation did not exhibit the highest complex modulus instead a sample with a higher concentration of mineral was identified (5.8w/v% agarose and 25w/v% HA). Thus, demonstrating the importance of examining the mechanical behaviour of biomaterials under conditions representative of physiological environments. While the complex moduli of the optimised gellan (1.0 ± 0.2MPa at 1Hz) and agarose (1.7 ± 0.2MPa at 1Hz) constructs did not match the complex moduli of healthy human cartilage samples (26.3 ± 6.5MPa at 1Hz), similar tan δ values were observed between 1 and 5Hz. This is promising since these frequencies represent the typical heel strike time of the general population. In summary, this study demonstrates the importance of considering more than just the strength of biomaterials since tissues like cartilage play a more complex role.

Scant research attention has been devoted to the phenomenon of multimodal hallucinations, with majority of studies focusing on auditory hallucinations (AH) in psychosis. The current study aimed to explore the frequency and characteristics of these multisensory hallucinations in a primary AH cohort. It was concluded more than half of our sample reported comorbid hallucinations in one or more sensory modes. This conveys significant research and clinical implications, in terms of steps taken for adequate assessment and intervention.

Background: Synovial inflammation is associated with pain severity in patients with knee osteoarthritis (OA). The aim here was to determine in a population with knee OA, whether synovial tissue from areas associated with pain exhibited different synovial fibroblast subsets, compared to synovial tissue from sites not associated with pain. A further aim was to compare differences between early and end-stage disease synovial fibroblast subsets. Methods: Patients with early knee OA (n=29) and end-stage knee OA (n=22) were recruited. Patient reported pain was recorded by questionnaire and using an anatomical knee pain map. Proton density fat suppressed MRI axial and sagittal sequences were analysed and scored for synovitis. Synovial tissue was obtained from the medial and lateral parapatellar and suprapatellar sites. Fibroblast single cell RNA sequencing was performed using Chromium 10X and analysed using Seurat. Transcriptomes were functionally characterised using Ingenuity Pathway Analysis and the effect of fibroblast secretome on neuronal growth assessed using rat DRG. Findings: Parapatellar synovitis was significantly associated with the pattern of patient-reported pain in knee OA patients. Synovial tissue from sites of patient-reported pain exhibited a differential transcriptomic phenotype, with distinct synovial fibroblast subsets in early OA and end-stage OA. Functional pathway analysis revealed that synovial tissue and fibroblast subsets from painful sites promoted fibrosis, inflammation and the growth and activity of neurons. The secretome of fibroblasts from early OA painful sites induced neurite outgrowth in dorsal root ganglion neurons. Interpretation: Sites of patient-reported pain in knee OA exhibit a different synovial tissue phenotype and distinct synovial fibroblast subsets. Further interrogation of these fibroblast pathotypes will increase our understanding of the role of synovitis in OA joint pain and provide a rationale for the therapeutic targeting of fibroblast subsets to alleviate pain in patients. Funding: This study was funded by Versus Arthritis (21530; 21812). Declaration of Interest: The authors declare no competing interests Ethical Approval: Ethical approval was granted by the UK National Research Ethics Committee (NRES 17/SC/0456). Consent was provided by all patients.

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1–5 and 8–12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307–15. ©2017 AACR.

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11–Rad51–DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair ‘addiction’ and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Diffusion tensor imaging studies report childhood adversity (CA) is associated with reduced fractional anisotropy (FA) in multiple white matter tracts in adults. Reduced FA may result from changes in tissue, suggesting myelin/axonal damage, and/or from increased levels of extracellular free-water, suggesting atrophy or neuroinflammation. Free-water imaging can separately identify FA in tissue (FA(T)) and the fractional volume of free-water (FW). We tested whether CA was associated with altered FA, FA(T), and FW in seven white matter regions of interest (ROI), in which FA changes had been previously linked to CA (corona radiata, corpus callosum, fornix, cingulum bundle: hippocampal projection, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus). Tract-based spatial statistics were performed in 147 psychiatrically healthy adults who had completed a self-report questionnaire on CA primarily stemming from parental maltreatment. ROI were extracted according to the protocol provided by the ENIGMA-DTI working group. Analyses were performed both treating CA as a continuous and a categorical variable. CA was associated with reduced FA in all ROI (although categorical analyses failed to find an association in the fornix). In contrast, CA was only associated with reduced FA(T) in the corona radiata, corpus callosum, and uncinate fasciculus (with the continuous measure of CA finding evidence of a negative relation between CA and FA(T) in the fornix). There was no association between CA on FW in any ROI. These results provide preliminary evidence that childhood adversity is associated with changes to the microstructure of white matter itself in adulthood. However, these results should be treated with caution until they can be replicated by future studies which address the limitations of the present study.

By interacting with proteins and nucleic acids, the vast family of mammalian circRNAs is proposed to influence many biological processes. Here, RNA sequencing analysis of circRNAs differentially expressed during myogenesis revealed that circSamd4 expression increased robustly in mouse C2C12 myoblasts differentiating into myotubes. Moreover, silencing circSamd4, which is conserved between human and mouse, delayed myogenesis and lowered the expression of myogenic markers in cultured myoblasts from both species. Affinity pulldown followed by mass spectrometry revealed that circSamd4 associated with PURA and PURB, two repressors of myogenesis that inhibit transcription of the myosin heavy chain (MHC) protein family. Supporting the hypothesis that circSamd4 might complex with PUR proteins and thereby prevent their interaction with DNA, silencing circSamd4 enhanced the association of PUR proteins with the Mhc promoter, while overexpressing circSamd4 interfered with the binding of PUR proteins to the Mhc promoter. These effects were abrogated when using a mutant circSamd4 lacking the PUR binding site. Our results indicate that the association of PUR proteins with circSamd4 enhances myogenesis by contributing to the derepression of MHC transcription.

Hallucinations can occur in different sensory modalities within an individual, both simultaneously and serially in time. Historically, they have typically been studied in clinical populations as phenomena occurring in a single sensory modality. Yet, hallucinatory experiences that occur in two or more sensory systems - multimodal hallucinations (MMHs) - are more prevalent than previously thought, and may have greater adverse impact than unimodal ones, but they remain relatively under-researched. Why people experience multi- modal hallucinations, what the implications for the person are, and how this could impact how such experiences are treated when distressing remain under-studied questions. Here, we review the available literature on MMHs and discuss some key concepts in the field, namely a) the definition and categorisation of both serial and simultaneous MMHs, b) which assessment tools are available and how they can be improved, and c) the explanatory power that current hallucination theories might have for MMHs. Overall, we suggest that current models need to be updated or developed in order to account for MMHs and to inform research into the underlying processes of such hallucinatory phenomena. We make recommendations for future research and clinical practice, highlighting the potential clinical impact of MMHs, the need for better assessment tools that can reliably measure MMHs and distinguish them from other related phenomena (such as delirium), as well as the need for service-user involvement in the validation of classification systems of MMHs.

BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Björnstad syndrome, characterized by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second patient was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients, and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient’s muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.

Key Points Question Is genetic liability for rheumatoid arthritis associated with cognitive and psychiatric phenotypes in children prior to the clinical onset of disease? Findings In this cohort study of 7977 children and adolescents, genetic liability for rheumatoid arthritis was associated with lower total, performance, and verbal IQ at age 8 years and symptoms of hyperactivity and inattention from ages 4 to 16 years. However, there was little evidence of association with other domains of psychopathology. Meaning These findings support a primary etiological association between genetic risk for rheumatoid arthritis and cognitive phenotypes that is not simply secondary to disease-related processes or reverse causation., This cohort study investigates whether genomic risk for rheumatoid arthritis is associated with cognitive and psychiatric symptoms in children and adolescents., Importance The association of rheumatoid arthritis (RA) with cognitive and psychiatric phenotypes has been recognized. However, it is not known whether these phenotypes are a consequence of disease-related factors, such as pain, or reflect shared etiological factors. Objective To investigate whether genomic risk for RA is associated with cognitive and psychiatric symptoms in children and adolescents. Design, Setting, and Participants This cohort study analyzed data from 3296 to 5936 adolescents (depending on outcome) from the Avon Longitudinal Study of Parents and Children. Clinical and questionnaire data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 21, 2017, to May 21, 2018. Exposures Polygenic risk scores (PRSs) for RA. Main Outcomes and Measures Measures of cognition (including IQ, working memory, verbal learning, processing speed, problem solving, selective attention, and attentional control) and psychopathology (including anxiety, depression, negative symptoms, psychotic experiences, attention-deficit/hyperactivity disorder, and hyperactive and inattentive symptoms) in childhood and adolescence. Results Polygenic risk scores for RA were generated for 7977 children and adolescents (3885 [48.7%] female). Of these 7977 participants, 9 (0.11%) had a known diagnosis of RA at age 22 years. Increased PRS for RA was associated with lower total IQ (β, −0.05; 95% CI, −0.07 to −0.02; P

Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11 beta-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11 beta-HSD1 activity ex vivo. Using the TNF-alpha-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11 beta-HSD1 global knock-out (11 beta KO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11 beta-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg(11 beta KO) mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg(11 beta KO) mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg(11 beta KO) compared to TNF-tg mice. In summary, 11 beta-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11 beta-HSD1 may offer a strategy to refine the safety of glucocorticoids.