Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD

A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa [version 1; referees: 2 approved]

Background: The pathogenesis of hidradenitis suppurativa (HS) remains unclear. In order to develop effective treatment strategies, a deeper understanding of pathophysiology is needed. This is impaired by multiple small studies with inconsistent methodologies and the impact of co-occurring pro-inflammatory conditions such as smoking and obesity. Methods: This systematic review aimed to collate all published reports of cytokine studies in tissue, blood, serum and exudate. It was registered with PROSPERO (Registration number CRD42018104664) performed in line with the PRISMA checklist. Results: 19 studies were identified comprising 564 individual HS patients and 198 control patients examining 81 discrete cytokines. Methodology was highly varied and the quality of studies was generally low. There was a large degree of variance between the measured levels of cytokines. 78.2% of cytokines demonstrated heterogeneity by the chi-squared test for homogeneity and hence meta-analysis was not deemed appropriate. However, a strong and significant IL-17 signalling component was identified. Conclusions: Cytokines consistently elevated in lesional, peri-lesional and unaffected tissue are identified and discussed. Areas for further investigation include the role of dendritic cells in HS; the contribution of obesity, smoking, diabetes and the microbiome to cytokine profiles in HS; and examining the natural history of this disease through longitudinal measurements of cytokines over time

The Impact of Body Mass Index Upon the Efficacy of Adalimumab in Hidradenitis Suppurativa

Elevated BMI in Hidradenitis Suppurativa is associated with decreased response to Adalimumab therapy. BMI is proposed to segregate distinct disease subtypes. It remains unresolved whether a threshold BMI exists above which increased dosages may provide clinical benefit. Individual patient data from 578 PIONEER Phase 3 participants were analyzed. Descriptive, multivariable regression analysis and receiver operating characteristic (ROC) curves were calculated to assess the relationship between BMI and clinical outcome measures using R v3.5.3. Participants in the overweight and obese BMI category had reduced odds (58 and 67%, respectively) of achieving HiSCR [OR = 0.42 (95%CI −0.19, 0.91) p = 0.03], [OR = 0.33 (95%CI 0.16, 0.67) p = 0.002] compared to participants with BMI < 25. Reduction in AN count and IHS4 score was not significantly associated. ROC analysis did not reveal any cut off value predictive of treatment outcome. No correlation between BMI and baseline disease activity or covariate interactions were identified. These findings suggest BMI is a significant covariate in the setting of lower baseline disease activity, supporting the concept of disease heterogeneity and differential therapeutic response to Adalimumab

The road to biologics in patients with hidradenitis suppurativa: a nationwide drug utilization study

Background: Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient's treatment journey leading to biologic therapy is unclear. Objectives: To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy. Methods: We identified all patients with HS receiving treatment with biologics in the Danish National Patient Registry from 2010 to 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995. The patients' treatment journeys are graphically displayed through Sankey diagrams and box plots generated to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with SDs or medians with interquartile ranges (IQRs) for continuous variables. Results: A total of 225 patients with HS were included. Patients had most frequently been treated with penicillin (n = 214; 95·1%), dicloxacillin (n = 194; 86·2%), tetracycline (n = 145; 64·4%) and rifampicin/clindamycin (n = 111; 49·3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4·0 (SD 1·3) different systemic therapies, across a mean of 16·9 (SD 11·3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15·3 (SD 5·1) years [8·2 (SD 5·9) years when excluding penicillin and dicloxacillin]. Conclusions: Patients with HS who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression. What is already known about this topic? The treatment journey leading to biologic therapy in patients with HS has not previously been investigated. What does this study add? Our data from 225 patients with HS illustrate that patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS

Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa:A randomized double-blind placebo-controlled clinical trial

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies. Objectives: To explore the effects of spesolimab treatment in patients with HS. Methods: This randomized double-blind placebo-controlled proof-of-clinical-concept (PoCC) study was conducted at 25 centres across 12 countries from 3 May 2021 to 21 April 2022. Patients had moderate-to-severe HS for ≥ 1 year before enrolment. Patients were randomized (2: 1) to receive a loading dose of 3600-mg intravenous spesolimab (1200 mg at weeks 0, 1 and 2) or matching placebo, followed by maintenance with either 1200-mg subcutaneous spesolimab every 2 weeks from weeks 4 to 10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at week 12. Secondary endpoints were the absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of 0, absolute change from baseline in the revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥ 1 flare (all at week 12) and patient-reported outcomes. Results: In this completed trial, randomized patients (n = 52) received spesolimab (n = 35) or placebo (n = 17). The difference vs. placebo in least squares mean is reported. At week 12, the percentage change in total AN count was similar between treatment arms: -4.1% [95% confidence interval (CI) -31.7 to 23.4]. There was greater numerical improvement in the spesolimab arm, as measured by IHS4 (13.9, 95% CI -25.6 to -2.3); percentage change from baseline in dT count (-96.6%, 95% CI -154.5 to -38.8); and the proportion of patients achieving a dT count of 0 (18.3%, 95% CI -7.9 to 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 vs. placebo. Spesolimab demonstrated a favourable safety profile, similar to that observed in trials in other diseases. Conclusions: This exploratory PoCC study supports the development of spesolimab as a new therapeutic option in HS.</p

Fluxes and gas transfer rates of the biogenic trace gas DMS derived from atmospheric gradients

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 109 (2004): C08S10, doi:10.1029/2003JC001795.Gas transfer rates were determined from vertical profile measurements of atmospheric dimethylsulfide (DMS) gradients over the equatorial Pacific Ocean obtained during the GasEx-2001 cruise. A quadratic relationship between gas transfer velocity and wind speed was derived from the DMS flux measurements; this relationship was in close agreement with a parameterization derived from relaxed eddy accumulation measurements of DMS over the northeastern Pacific Ocean. However, the GasEx-2001 relationship results in gas transfer rates that are a factor 2 higher than gas transfer rates calculated from a parameterization that is based on coincident eddy correlation measurements of CO2 flux. The measurement precision of both the profiling and eddy correlation techniques applied during GasEx-2001 is comparable; the two gas transfer data sets are in agreement within their uncertainty. Differences in the number of samples and the wind speed range over which CO2 and DMS fluxes were measured are likely causes for the observed discrepancy.Funding for this work came from the Netherlands Organization for Scientific Research (NWO) and from the NOP project 951203: ‘‘Micrometeorology of air/sea fluxes of carbon dioxide. This work was supported by the Global Carbon Cycle project of the NOAA Office of Global Programs grant NA17RJ1223, National Science Foundation grant OCE-9986724, and NSF grant ATM-0120569

The road to biologics in patients with hidradenitis suppurativa - a nationwide drug utilization study

Background Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). While biologic therapies are now available, the patient’s treatment journey leading to biologic therapy is unclear. Objectives To examine treatment patterns and duration of systemic treatment use in HS patients preceding biologic therapy. Methods We identified all HS patients receiving treatment with biologics in the Danish National Patient Registry from 2010 through 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995.The patients’ treatment journeys were graphically displayed through Sankey diagrams, and generated box-plots to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with standard deviations (SDs) or medians with interquartile ranges (IQRs) for continuous variables. Results A total of 225 HS patients were included. Patients had most frequently been treated with penicillin (n=214; 95.1%), dicloxacillin (n=194; 86.2%), tetracycline (n=145; 64.4%) and rifampicin/clindamycin (n=111; 49.3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4.0 (SD 1.3) different systemic therapies, across a mean of 16.9 (SD 11.3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15.3 (SD 5.1) years (8.2 [SD 5.9] years when excluding penicillin and dicloxacillin). Conclusion HS patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression

Rain-induced turbulence and air-sea gas transfer

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): C07009, doi:10.1029/2008JC005008.Results from a rain and gas exchange experiment (Bio2 RainX III) at the Biosphere 2 Center demonstrate that turbulence controls the enhancement of the air-sea gas transfer rate (or velocity) k during rainfall, even though profiles of the turbulent dissipation rate ɛ are strongly influenced by near-surface stratification. The gas transfer rate scales with ɛ inline equation for a range of rain rates with broad drop size distributions. The hydrodynamic measurements elucidate the mechanisms responsible for the rain-enhanced k results using SF6 tracer evasion and active controlled flux technique. High-resolution k and turbulence results highlight the causal relationship between rainfall, turbulence, stratification, and air-sea gas exchange. Profiles of ɛ beneath the air-sea interface during rainfall, measured for the first time during a gas exchange experiment, yielded discrete values as high as 10−2 W kg−1. Stratification modifies and traps the turbulence near the surface, affecting the enhancement of the transfer velocity and also diminishing the vertical mixing of mass transported to the air-water interface. Although the kinetic energy flux is an integral measure of the turbulent input to the system during rain events, ɛ is the most robust response to all the modifications and transformations to the turbulent state that follows. The Craig-Banner turbulence model, modified for rain instead of breaking wave turbulence, successfully predicts the near-surface dissipation profile at the onset of the rain event before stratification plays a dominant role. This result is important for predictive modeling of k as it allows inferring the surface value of ɛ fundamental to gas transfer.This work was funded by a generous grant from the David and Lucile Packard Foundation and the Lamont-Doherty Earth Observatory Climate Center. Additional funding was provided by the National Science Foundation (OCE-05-26677) and the Office of Naval Research Young Investigator Program (N00014-04-1-0621)