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Objectives: Very little is known on the efficacy and safety of drugs for the management of chronic calcium pyrophosphate (CPP) crystal inflammatory arthritis. The objectives of this work were to describe the drugs used in the management of chronic CPP crystal inflammatory arthritis in expert European centres, and to examine treatment retention., Methods: This was a retrospective cohort study. Charts from patients with a diagnosis of persistent inflammatory and/or recurrent acute CPP crystal arthritis were reviewed in seven European centres. Baseline characteristics were collected, and visits at months 3, 6, 12 and 24 included an assessment of treatment response and safety., Results: One hundred and ninety-four treatments were initiated in 129 patients. Colchicine (used first-line in n = 73/86), methotrexate (used first-line in n = 14/36), anakinra (n = 27) and tocilizumab (n = 25) were the most prescribed treatments, while long-term corticosteroids, hydroxychloroquine, canakinumab and sarilumab were used occasionally. The 24-month on-drug retention was higher for tocilizumab (40%) than anakinra (18.5%) (P < 0.05), while the difference between colchicine (29.1%) and methotrexate (44.4%) was not statistically significant (P = 0.10). Adverse events led to 14.1% of colchicine discontinuations (100% of diarrhoea), 4.3% for methotrexate, 31.8% for anakinra and 20% for tocilizumab; all other discontinuations were related to insufficient response or losses to follow-up. Efficacy outcomes did not differ significantly between treatments throughout follow-up., Conclusion: Daily colchicine is the first-line therapy used in chronic CPP crystal inflammatory arthritis, which is considered efficient in a third to half of cases. Second-line treatments include methotrexate and tocilizumab, which have higher retention than anakinra., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The human microbiome has emerged as a rich source of diverse and bioactive natural products, harboring immense potential for therapeutic applications. To facilitate systematic exploration and analysis of its biosynthetic landscape, we present ABC-HuMi: the Atlas of Biosynthetic Gene Clusters (BGCs) in the Human Microbiome. ABC-HuMi integrates data from major human microbiome sequence databases and provides an expansive repository of BGCs compared to the limited coverage offered by existing resources. Employing state-of-the-art BGC prediction and analysis tools, our database ensures accurate annotation and enhanced prediction capabilities. ABC-HuMi empowers researchers with advanced browsing, filtering, and search functionality, enabling efficient exploration of the resource. At present, ABC-HuMi boasts a catalog of 19 218 representative BGCs derived from the human gut, oral, skin, respiratory and urogenital systems. By capturing the intricate biosynthetic potential across diverse human body sites, our database fosters profound insights into the molecular repertoire encoded within the human microbiome and offers a comprehensive resource for the discovery and characterization of novel bioactive compounds. The database is freely accessible at https://www.ccb.uni-saarland.de/abc&#95;humi/., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Perioperative steroid administration may improve postoperative outcomes in major abdominal surgery by reducing the systemic inflammatory response. The aim of this systematic review was to evaluate the impact of perioperative steroid administration on outcomes after elective liver resection., Methods: PubMed, Cochrane Library, and Web of Science were systematically searched for randomized clinical trials (RCTs) comparing perioperative steroid administration with placebo, standard of care, or no steroids with respect to postoperative outcomes, particularly postoperative complications. Two independent reviewers critically appraised the studies and extracted data. Meta-analyses were performed using a random-effects model with ORs calculated for dichotomous outcomes and mean differences (MDs) for continuous outcomes., Results: Ten RCTs comprising 930 patients were included. Perioperative steroid administration significantly reduced the overall postoperative complication rate (OR 0.61, 95 per cent c.i. 0.43 to 0.87; P = 0.006; I2 = 26 per cent). No significant differences were shown for individual complications. Several postoperative laboratory parameters were positively affected, like total serum bilirubin (MD -0.46; 95 per cent c.i. -0.74 to -0.18; P = 0.001; I2 = 80 per cent), interleukin 6 (MD -48.99; 95 per cent c.i. -60.72 to -37.27; P < 0.001; I2 = 0 per cent) and C-reactive protein (MD -5.20; 95 per cent c.i. -7.62 to -2.77; P < 0.001; I2 = 71 per cent). There were no signs of an increase in potential steroid-induced adverse events, namely infectious complications, thromboembolic events, or bleeding., Conclusions: Perioperative steroid administration significantly reduces the overall complication rate after elective liver resection without an increased risk of adverse effects., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: In 2006, the Swiss Federal Office of Public Health (FOPH) decided recommending a prolongation of vaccine booster intervals after the third dose for the prevention of tick-borne encephalitis (TBE) from 3 to 10 years., Methods: To ascertain whether this amendment resulted in an increased rate of vaccine breakthroughs, we conducted a retrospective analysis of surveillance data collected 2000-19 by mandatory reporting to the Swiss FOPH. Fractions of breakthroughs [with 95% confidence intervals (CIs)]-0-3 years vs >3-10 years after the third vaccination dose-were compared across time periods and age groups., Results: Among 3205 notified TBE cases, known vaccination status was reported in 2562 (79.9%), including 103 patients with ≥3 vaccine doses (4.0%). Among those, there were 39 patients who had received the last dose within 3 years and 48 patients in the >3-10 years group. During the 2010-19 period in which the new booster strategy was implemented there were 23 and 38 breakthroughs, respectively, and the annual breakthrough rate was 7.7 (95% CI 5.0-11.7) cases during the first 3 years after the last dose, and 5.4 (95% CI 3.9-7.5) cases in following 7 years. We observed no significant trend of TBE breakthroughs with increasing age. Increasing numbers of TBE and of vaccine breakthroughs over time have been associated with spreading endemicity and higher vaccination coverage in Switzerland., Conclusions: There is no indication that extended booster intervals resulted in an increased rate of breakthroughs, but there was a marked public health benefit with respect to increased acceptability of TBE immunization in the general population., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as "premature adrenarche." It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene., Learning Objectives: Identify the precise pathophysiologic mechanisms leading to virilization in girls at puberty considering that virilization at puberty may be the first manifestation of an endocrine active tumor or a disorder/difference of sex development (DSD) that remained undiagnosed before and may be life-threatening. Of the DSDs, nonclassical congenital adrenal hyperplasia occurs most often.Provide a step-by-step diagnostic workup plan including repeated and expanded biochemical and genetic tests to solve complex cases.Manage clinical care of a girl virilizing at puberty using an interdisciplinary team approach.Care for complex cases of DSD manifesting at puberty, such as the presented girl with a Turner syndrome-like phenotype and virilization resulting from a complex genetic variation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia., Objectives: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs)., Design, Setting: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018., Patients and Methods: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia., Results: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia., Conclusions: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective was to determine the proportion of patients with difficult-to-treat or difficult-to-prevent acute gout attacks eligible for IL-1 inhibition., Methods: Participants included in the French cross-sectional GOSPEL cohort (n = 1003 gout patients) were examined for contraindications and intolerance to standard of care (SoC) drugs of gout flares (colchicine, non-steroidal anti-inflammatory drugs and systemic glucocorticoids). Patients were classified as definitely eligible for first-line IL-1 inhibition (canakinumab) according to European summary of product characteristics (contraindications/intolerance to SoC and at least three flares per year) without any other anti-inflammatory options (contraindications/intolerance only), or potentially eligible (precaution of use). Eligibility to receive IL-1 during an on-going flare related to insufficient efficacy was assessed (second-line eligibility)., Results: Definite first-line eligibility for IL-1 therapy was found in 10 patients (1%) and contraindication to all SoC therapies in nine patients who had presented <3 flares in the past 12 months. At least precaution of use for SoC therapies was noted for 218/1003 patients (21.7%). Of 487 patients experiencing flares at baseline, 114 (23.4%) were still experiencing pain scored ⩾4/10 numeric scale on day 3, one of whom could not receive further SoC drugs. Only nine of them had three or more flares in the past year and were eligible for second-line IL-1 inhibition., Conclusion: Despite significant numbers of patients without any SoC anti-inflammatory therapeutic options for gout flares, eligibility for IL-1 inhibition therapy according to current European approval is rare., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The binary sign, a binary appearance of the left ventricular endocardial border, was suggested to be an echocardiographic hallmark in diagnosing Fabry disease, a hereditary, lysosomal storage disorder. The aim of the present study was to examine the reliability of the binary sign as a screening tool to identify patients with Fabry disease., Methods and Results: In total 309 subjects with an interventricular septum (IVS) thickness of ≥12 mm were investigated, of which 14 had a confirmed diagnosis of Fabry disease. Urinary globotriaosylceramide testing was used to rule out Fabry disease in the control group. From all patients echocardiographic images of the apical four-chamber view were analysed offline by a blinded observer. A binary sign was seen in 63 patients (20%), 4 had Fabry disease and 59 belonged to the control group. Although the proportion of binary signs in patients with Fabry disease was higher (29%) compared with the control group (20%) this difference was not statistically significant. The sensitivity and specificity were 28% (95% confidence interval (CI): 12-65%) and 80% (95% CI: 76-85%), respectively. In a logistic regression model adjusted for age, sex and presence of Fabry disease, the occurrence of a binary sign was highly dependent on the IVS thickness (odds ratio: 1.21; 95% CI: 1.1-1.35; P<0.001)., Conclusion: The endocardial binary appearance is associated with the degree of septal hypertrophy but cannot adequately distinguish between patients with Fabry disease and patients with other causes of left ventricular hypertrophy.

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases, and other information for chordate, selected model organism and disease vector genomes. As of release 51 (November 2008), Ensembl fully supports 45 species, and three additional species have preliminary support. New species in the past year include orangutan and six additional low coverage mammalian genomes. Major additions and improvements to Ensembl since our previous report include a major redesign of our website; generation of multiple genome alignments and ancestral sequences using the new Enredo-Pecan-Ortheus pipeline and development of our software infrastructure, particularly to support the Ensembl Genomes project (http://www.ensemblgenomes.org/).

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of chordate genome sequences. Over the past year the number of genomes available from Ensembl has increased from 15 to 33, with the addition of sites for the mammalian genomes of elephant, rabbit, armadillo, tenrec, platypus, pig, cat, bush baby, common shrew, microbat and european hedgehog; the fish genomes of stickleback and medaka and the second example of the genomes of the sea squirt (Ciona savignyi) and the mosquito (Aedes aegypti). Some of the major features added during the year include the first complete gene sets for genomes with low-sequence coverage, the introduction of new strain variation data and the introduction of new orthology/paralog annotations based on gene trees.

Background: Intracranial saccular aneurysms (ICA) are a known extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). In order to facilitate the definition of subgroups who are at risk for ICA and to determine the prevalence of ICA in these subgroups we studied ADPKD patients with a positive family history for a cerebral event, including cerebral stroke (group I) and intracranial bleeding or known ICA (group II)., Methods: Within an enrolment period of 21 months, 43 ADPKD patients from our outpatient clinic and hospital were examined with cerebral magnetic resonance angiography (MRA)., Results: ICA were detected in six patients (14%). Three out of 32 patients (9.4%) in group I and three out of 11 patients (27.3%) in group II had an ICA. A dolichoectasia of intracerebral vessels was found in two out of 43 patients (4.7%)., Conclusions: Using MRA a high prevalence of ICA was shown only in patients with a family history of cerebral bleeding or ICA. A family history for cerebral stroke does not imply an elevated risk for ICA. However, dolichoectasia, rare in the normal population, was detected in two patients. We recommend screening for ICA in patients with a positive family history for cerebral bleeding or ICA. Because of potential complications, examiners should direct their attention to dolichoectasia in ADPKD patients.

Clinical and experimental data have shown that after acute myocardial infarction there is a significant release of tumour necrosis factor alpha. Therefore, an attempt was made to correlate changes in serum tumour necrosis factor alpha concentrations with indices of infarct extent in patients with acute myocardial infarction. In 50 patients with acute myocardial infarction, blood samples for evaluation of tumour necrosis factor alpha and alpha-hydroxybutyrate-dehydrogenase were collected every 6 h until 120 h after admission. Infarct extent was estimated by clinical parameters such as the occurrence of heart failure and rhythm disturbances, by enzymatic methods such as cumulative release of alpha-hydroxybutyrate-dehydrogenase and imaging techniques, by late resting single photon emission tomography--201 thallium scintigraphy--using an extent score and by echocardiography using a wall motion index. The maximum change in serum tumour necrosis factor alpha after infarction (delta TNF) was calculated by subtracting tumour necrosis factor alpha concentration on admission from peak tumour necrosis factor alpha concentration. The average peak tumour necrosis factor alpha level was observed 84 h after admission (median: 12 pg.ml-1). Between the 72nd and the 96th h no significant changes in tumour necrosis factor alpha values were observed. Analysis of the data showed that larger delta (TNF) values were found to be associated significantly with signs of heart failure (P = 0.003), the presence of rhythm disturbances (P = 0.001), increased enzymatic infarct extent indicated by cumulative release of alpha-hydroxybutyrate-dehydrogenase (r = 0.74; P < 0.001), large myocardial perfusion defects measured with 201 thallium scintigraphy (r = 0.80; P < 0.001), and a considerable number of left ventricular wall motion abnormalities (r = 0.57; P < 0.001). In conclusion, delta (TNF) is a reliable method of assessing damage severity in the myocardium after acute myocardial infarction. As only two blood samples are necessary within 84 h, the method may be one of the more convenient for the assessment of infarct size in clinical practice.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.