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Surgical wound excision is a necessary procedure for burn patients that require the removal of eschar. The extent of excision is currently guided by clinical judgement, with excessinto healthy tissue potentially leading to excessive scar, or inadequate debridement increasing risk of infection. Thus, an objective real-time measure to facilitate accurate excision could support clinical judgement and improve this surgical procedure. This study was designed to investigate the potential use of Rapid evaporative ionisation mass spectrometry (REIMS) as a tool to support data-driven objective tissue excision.Data were acquired using a multi-platform approach that consisted of both Rapid Evaporative Ionisation Mass Spectrometry (REIMS) performed on intact skin, and comprehensive liquid chromatography-mass spectrometry (LC-MS/MS) lipidomics performed on homogenised skin tissue extracts. Data were analysed using principal components analysis (PCA) and multivariate orthogonal projections to latent squares discriminant analysis (OPLS-DA) and logistic regression to determine the predictability of the models.PCA and OPLS-DA models of the REIMS and LC-MS/MS lipidomics data reported separation of excised and healthy tissue. Molecular fingerprints generated from REIMS analysis of healthy skin tissue revealed a high degree of heterogeneity, however, intra-individual variance was smaller than inter-individual variance. Both platforms indicated high levels of skin classification accuracy. In addition, OPLS-DA of the LC-MS/MS lipidomic data revealed significant differences in specific lipid classes between healthy control and excised skin samples; including lower free fatty acids (FFA), monoacylglycerols (MAG), lysophosphatidylglycerol (LPG) and lysophosphatidylethanolamines (LPE) in excised tissue and higher lactosylceramides (LCER) and cholesterol esters (CE) compared to healthy control tissue.Having established the heterogeneity in the biochemical composition of healthy skin using REIMS and LC-MS/MS, our data show that REIMS has the potential to distinguish between excied and healthy skin tissue samples. This pilot study suggests that REIMS may be an effective tool to support accurate tissue excision during burn surgery.

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2 p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.

Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy.

We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer’s ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.

UBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated withWe describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygousThis report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Epistemic injustice occurs when therapists implicitly and explicitly impose professional and institutional power onto clients. When clients have a diagnosis of schizophrenia, this very fact further complicates and highlights the power disparity within the helping relationship. Inspired by the work of critical philosopher Miranda Fricker on epistemic injustice, and using critical theories of language and knowledge, this article analyzes audiotaped session transcripts between a client with a history of psychosis and a social worker in an outpatient mental health agency. Findings illustrate two main discursive interactional patterns in everyday clinical social work encounters: (1) how the therapist's utterances claim disciplinary power and construct the client's testimony in alignment with an institutional agenda, while pre-empting the client's lived experience; and (2) how the client, though actively resisting, is managed to perform the identity of being a mentally ill person. The authors close with suggestions of how to avoid these mishaps and work toward epistemic justice in mental health practice.

Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Results of two clinical studies support the use of a carbohydrate-electrolyte beverage to improve performance of intermittent moderate- to high-intensity exercise, such as soccer and ice hockey. Two other studies documented that such beverages improved performance during steady-state moderate- to high-intensity exercise, although the mechanism by which carbohydrate improved performance in these protocols is yet to be determined.