An investigation of autoantibodies to the melanin-concentrating hormone receptor 1 in vitiligo.

Vitiligo is an acquired depigmenting disorder characterised by the loss of functional melanocytes and of melanin from the cutaneous epidermis. A role for autoimmunity in vitiligo pathogenesis is supported by the presence of anti-melanocyte autoantibodies and autoreactive T lymphocytes in patients with the disorder. Recently, the melanin-concentrating hormone receptor 1 (MCHRI) has been identified as an autoantigen in vitiligo. The aim of this study was to characterise the properties of MCHR1 autoantibodies. The epitopes on MCHR1 that are recognised by autoantibodies in vitiligo patients were identified using recombinant receptor in radio-binding assays. Multiple regions of MCHR1, including regions between amino acids 1-138 and 139-298, were identified as binding sites for MCHR1 autoantibodies. In addition, biopanning of a phage-display MCHRI cDNA fragment library with vitiligo patient immunoglobulin G (IgG), identified more specifically the target sites of MCHRI autoantibodies. A stable Chinese hamster ovary cell line expressing MCHR1 was isolated. The cell line clearly showed expression of the receptor by flow cytometry. Stimulation of the cell line with melanin-concentrating hormone (MCH) reduced forskolinstimulated cyclic adenosine monophosphate levels and increased the levels of intracellular calcium, both indicative of MCHRI expression. Functional blocking of MCI-iR1 by receptor autoantibodies was investigated by measuring changes in intracellular calcium levels in response to MCH-stimulation of MCHRI-expressing cells that had been pre-incubated with vitiligo patient IgG. The results revealed that 10/18 (56%) of the vitiligo patient IgGs tested were able to block receptor function. In contrast, IgG from healthy controls and from patients with other autoimmune disease had no effect upon receptor function. This suggested that MCHR1 function blocking autoantibodies are specific to patients with vitiligo and are not present in patients with other autoimmune disease. The cell line expressing MCHR1 was also used to analyse MCHR1 autoantibodies for any immunological activities such as complement-fixation and antibody-dependent cell-mediated cytotoxicity (ADCC). None of the vitiligo patient sera tested appeared to have MCHRI autoantibodies that were able either to fix complement or mediate ADCC. This suggested that there are no such immunological activities against MCHR1. In conclusion, key findings from this study were that the MCHRI is an important autoantigen in vitiligo, with 56% of patients having function-blocking autoantibodies against the receptor, and that amino acids 1-138 and 139-298 are major epitopes for MCHR1 binding autoantibodies

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on measurement to maintain and improve quality of enhanced recovery pathways for elective colorectal surgery.

BACKGROUND: This article sets out a framework for measurement of quality of care relevant to enhanced recovery pathways (ERPs) in elective colorectal surgery. The proposed framework is based on established measurement systems and/or theories, and provides an overview of the different approaches for improving clinical monitoring, and enhancing quality improvement or research in varied settings with different levels of available resources. METHODS: Using a structure-process-outcome framework, we make recommendations for three hierarchical tiers of data collection. DISCUSSION: Core, Quality Improvement, and Best Practice datasets are proposed. The suggested datasets incorporate patient data to describe case-mix, process measures to describe delivery of enhanced recovery and clinical outcomes. The fundamental importance of routine collection of data for the initiation, maintenance, and enhancement of enhanced recovery pathways is emphasized

Unveiling the hidden universe with JWST: The contribution of dust-obscured galaxies to the stellar mass function at z∼3−8\mathbf{z\sim3-8}

The emergence of massive, optically-faint galaxies in infrared observations has revealed that our view of the high-redshift Universe was previously incomplete. With the advent of JWST, we can for the first time probe the rest-frame optical emission of galaxies at $z>3$ with high sensitivity and spatial resolution, thus moving towards a more complete census of the galaxy population at high redshifts. To this end, we present a sample of 148 massive, dusty galaxies from the JWST/CEERS survey, colour-selected using solely JWST bands. With deep JWST/NIRCam data from 1.15$\mu$m to 4.44$\mu$m and ancillary HST/ACS and WFC3 data, we determine the physical properties of our sample using spectral energy distribution fitting with BAGPIPES. We demonstrate that our selection method efficiently identifies massive ($\mathrm{\langle \log M_\star/M_\odot \rangle \sim 10}$) and dusty ($\mathrm{\langle A_V\rangle \sim 2.7\ mag}$) sources, with a majority at $z>3$ and predominantly lying on the galaxy main-sequence. The main results of this work are the stellar mass functions (SMF) of red, optically-faint galaxies from redshifts between $3<z<8$: these galaxies make up a significant fraction of the pre-JWST total SMF at $3<z<4$, and dominate the high-mass end of the pre-JWST SMF at $4<z<6$ and $6<z<8$, suggesting that our census of the galaxy population needs amendment at these epochs. While larger areas need to be surveyed in the future, our results suggest already that the integrated stellar mass density at $\mathrm{\log M_\star/M_\odot>9.25}$ may have been underestimated by $\sim$20-25% at $z\sim3-6$, and $\sim$110% at $z\sim6-8$.Comment: 19 pages, 10 figures, submitted to MNRA

Ventilation and outcomes following robotic-assisted abdominal surgery: an international, multicentre observational study

Background: International data on the epidemiology, ventilation practice, and outcomes in patients undergoing abdominal robotic-assisted surgery (RAS) are lacking. The aim of the study was to assess the incidence of postoperative pulmonary complications (PPCs), and to describe ventilator management after abdominal RAS. Methods: This was an international, multicentre, prospective study in 34 centres in nine countries. Patients ≥18 yr of age undergoing abdominal RAS were enrolled between April 2017 and March 2019. The Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score was used to stratify for higher risk of PPCs (≥26). The primary outcome was the incidence of PPCs. Secondary endpoints included the preoperative risk for PPCs and ventilator management. Results: Of 1167 subjects screened, 905 abdominal RAS patients were included. Overall, 590 (65.2%) patients were at increased risk for PPCs. Meanwhile, 172 (19%) patients sustained PPCs, which occurred more frequently in 132 (22.4%) patients at increased risk, compared with 40 (12.7%) patients at lower risk of PPCs (absolute risk difference: 12.2% [95% confidence intervals (CI), 6.8–17.6%]; P&lt;0.001). Plateau and driving pressures were higher in patients at increased risk, compared with patients at low risk of PPCs, but no ventilatory variables were independently associated with increased occurrence of PPCs. Development of PPCs was associated with a longer hospital stay. Conclusions: One in five patients developed one or more PPCs (chiefly unplanned oxygen requirement), which was associated with a longer hospital stay. No ventilatory variables were independently associated with PPCs. Clinical trial registration: NCT02989415

Scalable noninvasive amplicon-based precision sequencing (SNAPseq) for genetic diagnosis and screening of β-thalassemia and sickle cell disease using a next-generation sequencing platform

β-hemoglobinopathies such as β-thalassemia (BT) and Sickle cell disease (SCD) are inherited monogenic blood disorders with significant global burden. Hence, early and affordable diagnosis can alleviate morbidity and reduce mortality given the lack of effective cure. Currently, Sanger sequencing is considered to be the gold standard genetic test for BT and SCD, but it has a very low throughput requiring multiple amplicons and more sequencing reactions to cover the entire HBB gene. To address this, we have demonstrated an extraction-free single amplicon-based approach for screening the entire β-globin gene with clinical samples using Scalable noninvasive amplicon-based precision sequencing (SNAPseq) assay catalyzing with next-generation sequencing (NGS). We optimized the assay using noninvasive buccal swab samples and simple finger prick blood for direct amplification with crude lysates. SNAPseq demonstrates high sensitivity and specificity, having a 100% agreement with Sanger sequencing. Furthermore, to facilitate seamless reporting, we have created a much simpler automated pipeline with comprehensive resources for pathogenic mutations in BT and SCD through data integration after systematic classification of variants according to ACMG and AMP guidelines. To the best of our knowledge, this is the first report of the NGS-based high throughput SNAPseq approach for the detection of both BT and SCD in a single assay with high sensitivity in an automated pipeline

Unveiling the nature of infrared bright, optically dark galaxies with early JWST data

Over the last few years, both Atacama Large Millimeter/submillimeter Array (ALMA) and Spitzer observations have revealed a population of likely massive galaxies at z > 3 that was too faint to be detected in Hubble Space Telescope (HST) rest-frame ultraviolet imaging. However, due to the very limited photometry for individual galaxies, the true nature of these so-called HSTdark galaxies has remained elusive. Here, we present the first sample of such galaxies observed with very deep, high-resolution NIRCam imaging from the Early Release Science programme CEERS. 30 HST-dark sources are selected based on their red colours across 1.6–4.4 μm. Their physical properties are derived from 12-band multiwavelength photometry, including ancillary HST imaging. We find that these galaxies are generally heavily dust-obscured (AV ∼ 2 mag), massive (log (M/M☉) ∼ 10), star-forming sources at z ∼ 2-8 with an observed surface density of ∼0.8 arcmin-2. This suggests that an important fraction of massive galaxies may have been missing from our cosmic census at z > 3 all the way into the Epoch of Reionization. The HST-dark sources lie on the main sequence of galaxies and add an obscured star formation rate density of 3.2+1.8-1.3 × 10-3 M☉ yr-1 Mpc-3 at z ∼ 7, showing likely presence of dust in the Epoch of Reionization. Our analysis shows the unique power of JWST to reveal this previously missing galaxy population and to provide a more complete census of galaxies at z = 2-8 based on rest-frame optical imaging

A systematic review and consensus definitions for standardised end-points in perioperative medicine: pulmonary complications

BackgroundThere is a need for robust, clearly defined, patient-relevant outcome measures for use in randomised trials in perioperative medicine. Our objective was to establish standard outcome measures for postoperative pulmonary complications research