bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic review of 454 randomized controlled trials using the Dermatology Life Quality Index: experience in 69 diseases and 43 countries
Authors: Vyas Jui , Johns Jeffrey R , Ali Faraz M , Singh Ravinder K , Ingram John R , Salek Sam , Finlay Andrew Y 
Published: March 2023

AbstractBackgroundOver 29 years of clinical application, the Dermatology Life Quality Index (DLQI) has remained the most used patient-reported outcome (PRO) in dermatology due to its robustness, simplicity and ease of use.ObjectivesTo generate further evidence of the DLQI's utility in randomized controlled trials (RCTs) and to cover all diseases and interventions.MethodsThe methodology followed PRISMA guidelines and included seven bibliographical databases, searching articles published from 1 January 1994 until 16 November 2021. Articles were reviewed independently by two assessors, and an adjudicator resolved any opinion differences.ResultsOf 3220 screened publications, 454 articles meeting the eligibility criteria for inclusion, describing research on 198 190 patients, were analysed. DLQI scores were primary endpoints in 24 (5.3%) of studies. Most studies were of psoriasis (54.1%), although 69 different diseases were studied. Most study drugs were systemic (85.1%), with biologics comprising 55.9% of all pharmacological interventions. Topical treatments comprised 17.0% of total pharmacological interventions. Nonpharmacological interventions, mainly laser therapy and ultraviolet radiation treatment, comprised 12.2% of the total number of interventions. The majority of studies (63.7%) were multicentric, with trials conducted in at least 42 different countries; 40.2% were conducted in multiple countries. The minimal clinically importance difference (MCID) was reported in the analysis of 15.0% of studies, but only 1.3% considered full score meaning banding of the DLQI. Forty-seven (10.4%) of the studies investigated statistical correlation of the DLQI with clinical severity assessment or other PRO/quality of life tools; and 61–86% of studies had within-group scores differences greater than the MCID in ‘active treatment arms’. The Jadad risk-of-bias scale showed that bias was generally low, as 91.8% of the studies had Jadad scores of ≥ 3; only 0.4% of studies showed a high risk of bias from randomization. Thirteen per cent had a high risk of bias from blinding and 10.1% had a high risk of bias from unknown outcomes of all participants in the studies. In 18.5% of the studies the authors declared that they followed an intention-to-treat protocol; imputation for missing DLQI data was used in 34.4% of studies.ConclusionsThis systematic review provides a wealth of evidence of the use of the DLQI in clinical trials to inform researchers’ and ­clinicians’ decisions for its further use. Recommendations are also made for improving the reporting of data from future RCTs using the DLQI.
Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype
Authors: Tagoe Hephzi , Hassan Sakinah , Bliss Emily , Youssef Gehad , Heywood Wendy , Mills Kevin , Harper John I , O’Shaughnessy Ryan F L 
Published: March 2023

Abstract

Background
Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales, often affecting the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterized; however, recent publications suggest that common mechanisms are active in ichthyotic tissue and in analogous models of ichthyosis.

Objectives
To determine common mechanisms of hyperkeratosis that may be easily targeted with small-molecule inhibitors.

Methods
We combined gene expression analysis of gene-specific short hairpin RNA (shRNA) knockdowns in rat epidermal keratinocytes (REKs) of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Tgm1 and Alox12b, and proteomic analysis of skin scale from patients with ARCI, as well as RNA sequencing data from rat epidermal keratinocytes treated with the Toll-like receptor 2 (TLR2) agonist Pam3CSK4.

Results
We identified common activation of the TLR2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and, in organotypic culture, caused hyperkeratosis. Conversely, blockade of TLR2 signalling in keratinocytes from patients with ichthyosis and our shRNA models reduced the expression of keratin 1, a structural protein overexpressed in ichthyosis scale. A time course of TLR2 activation in REKs revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread upregulation of epidermal differentiation-related proteins. Both nuclear factor kappa B phosphorylation and GATA3 upregulation was associated with this switch, and GATA3 overexpression was sufficient to increase keratin 1 expression.

Conclusions
Taken together, these data define a dual role for TLR2 activation during epidermal barrier repair that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.
Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study
Authors: Landis Megan N , Smith Stacy R , Berstein Gabriel , Fetterly Gerald , Ghosh Pranab , Feng Gang , Pradhan Vivek , Aggarwal Sudeepta , Banfield Christopher , Peeva Elena , Vincent Michael S , Beebe Jean S , Tarabar Sanela 
Published: March 2023

Abstract

Background
Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways.

Objectives
To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO.

Methods
This phase IIb multicentre randomized double-blind study was conducted in two stages. In stage 1, participants received one of eight treatments for 12 weeks: brepocitinib 0.1% once daily, 0.3% once or twice daily, 1.0% once or twice daily, 3.0% once daily, or vehicle once or twice daily. In stage 2, participants received brepocitinib 3.0% twice daily or vehicle twice daily. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment response [score of clear (0) or almost clear (1) and an improvement of ≥ 2 points from baseline] at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures, and the change from baseline in Peak Pruritus Numerical Rating Scale at week 12. Safety was monitored.

Results
Overall, 344 participants were randomized. Topical brepocitinib did not result in statistically significant changes compared with respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean change from baseline in PASI score ranged from –1.4 to –2.4 for the brepocitinib once-daily groups vs. –1.6 for vehicle once daily, and from –2.5 to –3.0 for the brepocitinib twice-daily groups vs. –2.2 for vehicle twice daily. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib twice daily groups. Brepocitinib was well tolerated, with adverse events (AEs) occurring at similar rates across groups. One participant in the brepocitinib 1.0% once-daily group developed a treatment-related AE of herpes zoster in the neck area.

Conclusions
Topical brepocitinib was well tolerated but did not result in statistically significant changes compared with vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO.
Diagnosis and treatment for gastro-oesophageal cancer in England and Wales: analysis of the National Oesophago-Gastric Cancer Audit (NOGCA) database 2012–2020
Authors: Pucher Philip H , Park Min Hae , Cromwell David A , Crosby Tom C , Thomas Betsan , Trudgill Nigel , Wahedally Muhammad , Maynard Nick , Gossage James A 
Published: March 2023

AbstractBackgroundThe National Oesophago-Gastric Cancer Audit (NOGCA) captures patient data from diagnosis to end of primary treatment for all patients with oesophagogastric (OG) cancer in England and Wales. This study assessed changes in patient characteristics, treatments received, and outcomes for OG cancer surgery for the period 2012–2020, and examined which factors may have led to changes in clinical outcomes over this time.MethodsPatients diagnosed with OG cancer between April 2012 and March 2020 were included. Descriptive statistics were used to summarize patient demographics, disease site, type, and stage, patterns of care, and outcomes over time. The treatment variables of unit case volume, surgical approach, and neoadjuvant therapy were included. Regression models were used to examine associations between surgical outcomes (duration of stay and mortality), and patient and treatment variables.ResultsIn total, 83 393 patients diagnosed with OG cancer during the study period were included. Patient demographics and cancer stage at diagnosis showed little change over time. Altogether, 17 650 patients underwent surgery as part of radical treatment. These patients had increasingly more advanced cancers, and a greater likelihood of pre-existing comorbidity in more recent years. Significant decreases in mortality rates and duration of stay were noted, along with improvements in oncological outcomes (nodal yields and margin positivity rates). Following adjustment for patient and treatment variables, increasing audit year and trust volume were associated, respectively, with improved postoperative outcomes: lower 30-day mortality (odds ratio (OR) 0.93 (95 per cent c.i. 0.88 to 0.98) and OR 0.99 (95 per cent c.i. 0.99–0.99)) and lower 90-day mortality (OR 0.94 (95 per cent c.i. 0.91 to 0.98) and OR 0.99 (95 per cent c.i. 0.99–0.99)), and a reduction in duration of postoperative stay (incidence rate ratio (IRR) 0.98 (95 per cent c.i. 0.97 to 0.98) and IRR 0.99 (95 per cent c.i. 0.99 to 0.99)).ConclusionOutcomes of OG cancer surgery have improved over time, despite little evidence of improvements in early diagnosis. The underlying drivers for improvements in outcome are multifactorial.
Sex differences in treatment and outcomes amongst myocardial infarction patients presenting with and without obstructive coronary arteries: a prospective multicentre study
Authors: Lawless Michael , Appelman Yolande , Beltrame John F , Navarese Eliano P , Ratcovich Hanna , Wilkinson Chris , Kunadian Vijay 
Published: March 2023

Abstract

Aims
Women have an increased prevalence of myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA). Whether sex differences exist in the outcomes of patients with MI and obstructive coronary arteries (MIOCA) vs. MINOCA remains unclear. We describe sex-based differences in diagnosis, treatment, and clinical outcomes of patients with MINOCA vs. MIOCA.

Methods and results
A large-scale cohort study of patients with ST/non-ST elevation MI undergoing coronary angiography (01/2015–12/2019). Patient demographics, diagnosis, prescribed discharge medications, in-hospital complications, and follow-up data were prospectively collected. A total of 13 202 participants were included (males 68.2% and females 31.8%). 10.9% were diagnosed with MINOCA. Median follow-up was 4.62 years. Females (44.8%) were as commonly diagnosed with MINOCA as males (55.2%), unlike the male preponderance in MIOCA (male, 69.8%; female, 30.2%). Less secondary prevention medications were prescribed at discharge for MINOCA than MIOCA. There was no difference in mortality risk between MINOCA and MIOCA [in-hospital: adjusted odds ratio (OR) 1.32, 95% confidence interval (CI) 0.74–2.35, P = 0.350; long term: adjusted hazard ratio (HR) 1.03, 95% CI 0.81–1.31, P = 0.813]. MINOCA patients had reduced mortality at long-term follow-up if prescribed secondary prevention medications (aHR 0.64, 95% CI 0.47–0.87, P = 0.004). Females diagnosed with MIOCA had greater odds of in-hospital and 1-year mortality than males (aOR 1.50, 95% CI 1.09–2.07, P = 0.014; aHR 1.18, 95% CI 1.01–1.38, P = 0.048).

Conclusion
MINOCA patients have similar mortality rates as MIOCA patients. MINOCA patients were less likely than those with MIOCA to be discharged with guideline-recommended secondary prevention therapy; however, those with MINOCA who received secondary prevention survived longer. Females with MIOCA experienced higher mortality rates vs. males.
LC-MS/MS Determination of Antibiotic Residues in Distillers Grains: Method Modification
Authors: De Alwis Hemakanthi G , Nochetto Cristina 
Published: March 2023

Abstract

Background
Antibiotics are used in ethanol production to discourage undesirable bacteria growth. To determine if antibiotic residues remain in the distillers grain (DG) byproduct, which is used as an animal food ingredient, the U.S. Food and Drug Administration/Center for Veterinary Medicine previously developed an LC-MS/MS method to detect residues of erythromycin A, penicillin G, virginiamycin M1, and virginiamycin S1 in DG to enable regulatory decision-making.

Objective
Erythromycin and penicillin G were quantitated using the stable isotope dilution technique with their isotopically labeled compounds, which are considered optimal internal standards (ISTDs) for quantitative mass spectrometry. With the commercial availability of virginiamycin M1-d2 since then, the objectives of this study were to evaluate the feasibility of its use as it is only doubly deuterated, and to incorporate it in the method to enhance method performance.

Method
Antibiotic residues were solvent-extracted from DG; the extract was cleaned up by a hexane wash and solid phase extraction (SPE) and analyzed by LC-MS/MS.

Results
We established suitability of virginiamycin M1-d2 as an ISTD and incorporated it in the method. For all analytes, accuracy and precision ranged 90 to 102% and 3.8 to 6.8, respectively.

Conclusions
We modified a previously developed LC-MS/MS method that uses virginiamycin M1-d2 as an ISTD to support surveillance studies to determine several drugs in DG.

Highlights
Virginiamycin M1-d2 was successfully incorporated into the method for better virginiamycin M1 quantitation. This addition also allowed calibration curves for all analytes to be constructed in solvent, thereby simplifying the method.
Ineffective investigation into making a book available for illegal download breaches copyright holder’s right to property, rules European Court of Human Rights
Authors: Izyumenko Elena 
Published: March 2023

Abstract
The European Court of Human Rights continues to establish breaches of copyright holders’ (human) right to property. This time, in a judgment from January 2023, the Court held that a protracted and ineffective investigation in respect of making the applicant’s book available for illegal download on the internet was in breach of the State’s positive obligation to protect intellectual property.
Vertical motion in the Galactic disc: unwinding the snail
Authors: Frankel Neige , Bovy Jo , Tremaine Scott , Hogg David W 
Published: March 2023

ABSTRACTThe distribution of stars in the Milky Way disc shows a spiral structure − the snail − in the space of velocity and position normal to the Galactic mid-plane. The snail appears as straight lines in the vertical frequency−vertical phase plane when effects from sample selection are removed. Their slope has the dimension of inverse time, with the simplest interpretation being the inverse age of the snail. Here, we devise and fit a simple model in which the spiral starts as a lopsided perturbation from steady state, that winds up into the present-day morphology. The winding occurs because the vertical frequency decreases with vertical action. We use data from stars in Gaia EDR3 that have measured radial velocities, pruned by simple distance and photometric selection functions. We divide the data into boxels of dynamical invariants (radial action, angular momentum); our model fits the data well in many of the boxels. The model parameters have physical interpretations: one, A, is a perturbation amplitude, and one, t, is interpretable in the simplest models as the time since the event that caused the snail. We find trends relating the strength and age to angular momentum: (i) the amplitude A is small at low angular momentum (${\lt 1\, 600{\,}kpc\ km\ s}^{-1}$ or guiding-centre radius $\lt 7.3\,$kpc) and over a factor of three larger, with strong variations, in the outer disc; (ii) there is no single well-defined perturbation time, with t varying between 0.2 and 0.6 Gyr. Residuals between the data and the model display systematic trends, implying that the data call for more complex models.
Stirred but not shaken: a multiwavelength view of HD 16743’s debris disc
Authors: Marshall Jonathan P , Milli J , Choquet E , del Burgo C , Kennedy G M , Kemper F , Wyatt M C , Kral Q , Soummer R 
Published: March 2023

ABSTRACT
Planetesimals – asteroids and comets – are the building blocks of planets in protoplanetary discs and the source of dust, ice, and gas in debris discs. Along with planets they comprise the left-over material after star formation that constitutes a planetary system. Planets influence the dynamics of planetesimals, sculpting the orbits of debris belts to produce asymmetries or gaps. We can constrain the architecture of planetary systems, and infer the presence of unseen planetary companions, by high spatial resolution imaging of debris discs. HD 16743 is a relatively young F-type star that hosts a bright edge-on debris disc. Based on far-infrared Herschel observations its disc was thought to be stirred by a planetary companion. Here, we present the first spatially resolved observations at near-infrared and millimetre wavelengths with HST and ALMA, revealing the disc to be highly inclined at $87{_{.}^{\circ}} 3~^{+1{_{.}^{\circ}} 9}_{-2{_{.}^{\circ}} 5}$ with a radial extent of 157.7$^{+2.6}_{-1.5}$ au and an full width at half maximum of 79.4$^{+8.1}_{-7.8}$ au (ΔR/R = 0.5). The vertical scale height of the disc is 0.13 ± 0.02, significantly greater than typically assumed unstirred value of 0.05, and could be indicative of stirring of the dust-producing planetesimals within the disc by bodies at least a few times the mass of Pluto up to 18.3 M⊕ in the single object limit.
Healthcare workers’ acceptance of and adherence to latent tuberculosis treatment
Authors: Yang H , Lee J S , Kim Y 
Published: March 2023

Abstract

Background
Healthcare workers (HCWs) with latent tuberculosis infection (LTBI) have a high risk of active tuberculosis and need systematic LTBI screening and treatment. However, acceptance and adherence rates of LTBI treatment are low.

Aims
To examine the specific reasons for the loss at each LTBI treatment-cascade stage: acceptance, continuation and completion of LTBI treatment in HCWs.

Methods
This retrospective descriptive study was conducted among 61 HCWs with an interferon-gamma release assay-confirmed LTBI diagnosis who were prescribed LTBI treatment at a tertiary hospital in the Republic of Korea. Data were analysed using Pearson’s chi-square, Fisher’s exact, independent t-test and Mann–Whitney U-test. A word cloud analysis was used to describe the perceived meaning of LTBI in HCWs.

Results
HCWs who refused or discontinued LTBI treatment perceived LTBI as ‘not a big deal’, whereas HCWs who completed LTBI treatment had a high-risk perception of the LTBI prognosis, such as ‘frightened about adverse prognosis’. Determinants of non-adherence to the recommended LTBI treatment included a busy work schedule, side effects of anti-tuberculosis agents and the inconvenience of regularly taking anti-tuberculosis agents.

Conclusions
To ensure LTBI treatment adherence in HCWs, effective interventions that are customized to each stage of the LTBI treatment should be developed, with due consideration of the stage-specific perceived facilitators and barriers in the LTBI treatment cascade.
Anaplastic large cell lymphoma ALK-positive variant of primary bone lymphoma associated with melanoma
Authors: Tutaeva Victoria V , Ovsiannikova Maria R , Bobin Alexander N , Gorbunov Alexey V , Kurbanov Sergey I , Rukavitsin Oleg A 
Published: March 2023

ABSTRACTWe describe in detail a case of the anaplastic large cell lymphoma (ALCL) type of primary bone lymphoma, which initially was diagnosed and treated as osteomyelitis. The diagnosis was delayed because of unspecific clinical symptoms and uncertain radiographs and histology. Only relapse of the lymphoma from the same area with involvement of the soft tissue and local lymph nodes allowed to establish a correct diagnosis and start treatment. Also, in this case, we observed the development of the second cancer (melanoma), which has the same cytogenetic abnormality as ALCL (t[2;5]).
Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity
Authors: Heyden Katarina E , Fiddler Joanna L , Xiu Yuwen , Malysheva Olga V , Handzlik Michal K , Phinney Whitney N , Stiles Linsey , Stabler Sally P , Metallo Christian M , Caudill Marie A , Field Martha S 
Published: March 2023

Abstract
Adequate thymidylate [deoxythymidine monophosphate (dTMP) or the “T” base in DNA] levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a “U” base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how reduced levels of the B12-dpendent enzyme methionine synthase (MTR) and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr+/+ and Mtr+/− mice weaned onto either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a folate-deficient (FD) diet (lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr+/− mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. Mtr+/− mice consuming the FD diet exhibited less uracil accumulation in liver mtDNA as compared to Mtr+/+ mice consuming the FD diet. Furthermore, Mtr+/− mice exhibited 25% lower liver mtDNA content and a 20% lower maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis, induced by decreased Mtr expression, also leads to increased uracil in mtDNA.