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Abstract Background Research investigating prognosis in musculoskeletal pain conditions has only been moderately successful in predicting which patients are unlikely to recover. Clinical decision making could potentially be improved by combining information taken at baseline and re-consultation. Methods Data from four prospective clinical cohorts of adults presenting to UK and Dutch primary care with low-back or shoulder pain was analysed, assessing long-term disability at 6 or 12 months and including baseline and 4–6 week assessments of pain. Baseline versus short-term assessments of pain, and previously validated multivariable prediction models versus repeat assessment, were compared to assess predictive performance of long-term disability outcome. A hypothetical clinical scenario was explored which made efficient use of both baseline and repeated assessment to identify patients likely to have a poor prognosis and decide on further treatment. Results Short-term repeat assessment of pain was better than short-term change or baseline score at predicting long-term disability improvement across all cohorts. Short-term repeat assessment of pain was only slightly more predictive of long-term recovery (c-statistics 0.78, 95% CI 0.74 to 0.83 and 0.75, 95% CI 0.69 to 0.82) than a multivariable baseline prognostic model in the two cohorts presenting such a model (c-statistics 0.71, 95% CI 0.67 to 0.76 and 0.72, 95% CI 0.66 to 0.78). Combining optimal prediction at baseline using a multivariable prognostic model with short-term repeat assessment of pain in those with uncertain prognosis in a hypothetical clinical scenario resulted in reduction in the number of patients with an uncertain probability of recovery, thereby reducing the instances where patients may be inappropriately referred or reassured. Conclusions Incorporating short-term repeat assessment of pain into prognostic models could potentially optimise the clinical usefulness of prognostic information.

Objectives. To investigate the course and prognosis of shoulder pain in the first 6 months after presentation to the general practitioner. We separately studied patients with acute, subacute and chronic shoulder pain, as duration of symptoms at presentation has been shown to be the strongest predictor of outcome. Methods. A prospective cohort study with 6 months follow-up was carried out in The Netherlands, including 587 patients with a new episode of shoulder pain. Patients were categorized as having acute (symptoms <6 weeks), subacute (6–12 weeks) or chronic (>3 months) shoulder pain. The course of shoulder pain, functional disability and quality of life was analysed over 6 months. Patient and disease characteristics, including physical and psychosocial factors, were investigated as possible predictors of outcome using multivariable regression analyses. Results. Acute shoulder symptoms showed the most favourable course over 6 months follow-up, with larger pain reduction and improvement of functional disability. Patients with chronic shoulder symptoms showed the poorest results. The multivariable regression analysis showed that predictors of a better outcome at 6 months for acute shoulder pain were lower baseline disability scores and higher baseline pain intensity (explained variance 46%). Predictors of a better outcome for chronic shoulder pain were lower scores on pain catastrophizing and higher baseline pain intensity (explained variance 21%). Conclusions. The results indicate that, besides a different course of symptoms in patients presenting with acute or chronic shoulder pain, predictors of outcome may also differ with psychosocial factors being more important in chronic shoulder pain. [ABSTRACT FROM AUTHOR]

Background: The recommendation to consider prescribing inhalation corticosteroids to a subgroup of vulnerable COVID-19 patients was added to the Dutch medical guideline on November 11, 2021, and was also adopted by other countries during the pandemic., Aim: To evaluate the adherence of general practitioners to this guideline, and whether real-world data quality is sufficient to study the effect of revised guidelines on prescribing behaviour., Design & Setting: A retrospective cohort study using Dutch primary care data from the Extramural LUMC Academic Network database, containing patient data of 129 general practices in the Leiden - The Hague area., Method: We performed an interrupted time series analysis to measure the effect of the new guideline on the prescription rate of ICS, accounting for general trend and seasonal fluctuations., Results: Between July 1, 2020 to August 1, 2022, 131,482 patients had 164,098 COVID-19 consultations. During this period, 1,709 patients received 2094 ICS prescriptions for COVID-19. After the guideline update, there was an instantaneous decrease in prescription rate (IRR 0.47, 95% CI 0.32-0.69). Prescription rate in the subgroup of vulnerable patients did not change significantly (IRR 0.93, 95% CI 0.66-1.32), while less vulnerable patients were significantly prescribed less (IRR 0.29, 95% CI 0.14-0.59)., Conclusion: The revision to COVID-19 guidelines had significant impact on general practitioners' prescription behaviour soon after publication: prescription rate remained constant for vulnerable patients, while less vulnerable patient were significantly prescribed less often. Using electronic health records it is feasible to assess changes in guideline adherence using interrupted time series., (Copyright © 2024, The Authors.)

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases., Methods: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness., Results: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock., Conclusion: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing., Methods: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification., Results: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category., Conclusions: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship., Competing Interests: Potential conflicts of interest. A. J. C. reports 2 grants from UK Research and Innovation (principal investigator), outside the submitted work, a grant from the National Institute of Health and Care Research (as joint lead of the Global Health Research Group), and a role as chair of the Committee for Scientific Affairs and Awards for European Society for Paediatric Infectious Disease. F. M-T. reports financial support for educational activities from Sanofi, MSD, Moderna, GlaxoSmithKline (GSK), Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer, outside the submitted work; travel expenses and meeting fees covered by Pfizer, MSD, GSK, and Sanofi; participation on a data safety monitoring board or advisory board for Pfizer and Biofabri; ; roles as coordinator of Spanish Pediatric Critical Trials Network and coordinator of the World Health Organization (WHO) Collaborating Centre for Vaccine Safety of Santiago de Compostela; and roles as principal investigator in randomized controlled trials for Ablynx, Abbott, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK. A. J. P. reports consulting fees from Shionogi, outside the submitted work; grants or contracts paid to the institution from the Bill & Melinda Gates Foundation, the Wellcome Trust, Cepi, the Medical Research Council, and the National Institute for Health and Care Research; royalties or licenses from AstraZeneca (Oxford University has entered into a partnership with AstraZeneca for development of coronavirus disease 2019 [COVID-19] vaccines); and unpaid roles as chair of the Department of Health and Social Care's Joint Committee on Vaccination and Immunisation and as a member of the WHO Strategic Advisory Group of Experts on Immunization (SAGE) until 2022. P. K. A. A. was a member of the Sanofi advisory board for nirsevimab in 2022. M. N. T. reports consulting fees for an MSD advisory board, support for attending IDWeek 2022 from Pfizer and IDWeek 2023 from Janssen, and unpaid participation on the Scientific Advisory Group of Experts for COVID-19 (Greece) and the National Committee for immunization Practices (Greece). U. v. B. reports financial support for educational activities (lectures on antimicrobial stewardship; pediatric educational curricula) from MSD, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Humoral responses after SARS-CoV-2 vaccination are greatly impaired in multiple sclerosis (MS) patients on fingolimod. Effects of repeated vaccination and infections on long-term responses are unclear., Methods: Prospective study in 60 MS patients on fingolimod measuring humoral responses after up to four vaccinations and 8 months after fourth vaccination., Results: Anti-WH1 antibody titers increased with each additional vaccination. At long-term follow-up titers increased further and most patients developed new humoral responses against the BA.1 omicron variant., Conclusion: Repeated SARS-CoV-2 vaccinations boost humoral immunity and, probably together with SARS-CoV-2 infections, induce humoral responses on the long-term in almost all patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FE and TK report (governmental) grants from ZonMw to study immune response after SARS-CoV-2 vaccination in auto-immune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSL Behring; honoraria from Grifols. JK has speaking relationships with Merck Serono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche, and Novartis; Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck Serono, Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Roche, Teva, Sanofi, Genzyme, GlaxoSmithKline, and Novartis. No other disclosures were reported.

The ability of the centrifugal Lab-on-a-Disc (LoaD) platform to closely mimic the "on bench" liquid handling steps (laboratory unit operations (LUOs)) such as metering, mixing, and aliquoting supports on-disc automation of bioassay without the need for extensive biological optimization. Thus, well-established bioassays, normally conducted manually using pipettes or using liquid handling robots, can be relatively easily automated in self-contained microfluidic chips suitable for use in point-of-care or point-of-use settings. The LoaD's ease of automation is largely dependent on valves that can control liquid movement on the rotating disc. The optimum valving strategy for a true low-cost and portable device is rotationally actuated valves, which are actuated by changes in the disc spin-speed. However, due to tolerances in disc manufacturing and variations in reagent properties, most of these valving technologies have inherent variation in their actuation spin-speed. Most valves are actuated through stepped increases in disc spin-speed until the motor reaches its maximum speed (rarely more than 6000 rpm). These manufacturing tolerances combined with this "analogue" mechanism of valve actuation limits the number of LUOs that can be placed on-disc. In this work, we present a novel valving mechanism called low-high-low serial dissolvable film (DF) valves. In these valves, a DF membrane is placed in a dead-end pneumatic chamber. Below an actuation spin-speed, the trapped air prevents liquid wetting and dissolving the membrane. Above this spin-speed, the liquid will enter and wet the DF and open the valve. However, as DFs take ∼40 s to dissolve, the membrane can be wetted, and the disc spin-speed reduced before the film opens. Thus, by placing valves in a series, we can govern on which "digital pulse" in spin-speeding a reagent is released; a reservoir with one serial valve will open on the first pulse, a reservoir with two serial valves on the second, and so on. This "digital" flow control mechanism allows the automation of complex assays with high reliability. In this work, we first describe the operation of the valves, outline the theoretical basis for their operation, and support this analysis with an experiment. Next, we demonstrate how these valves can be used to automate the solid-phase extraction of DNA on on-disc LAMP amplification for applications in plant pathogen detection. The disc was successfully used to extract and detect, from a sample lysed off-disc, DNA indicating the presence of thermally inactivated Clavibacter michiganensis ssp. michiganensis (Cmm) , a bacterial pathogen on tomato leaf samples., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Objective: Our objective is to develop a step-by-step approach for our institutes to evaluate the influence of the funding body 1. on risk of bias of an individual study and 2. on publication bias in reviews and meta-analyses for guidelines., Study Design and Setting: Methodologists from guideline organizations in the Netherlands discussed the influence of the funding body in clinical trials researching interventions. Results were discussed in our organizations and presented at the Dutch GRADE Network., Results: Two step-by-step approaches were developed to guide methodologists from our institutes in assessing the influence of the funding body 1. on risk of bias of an individual study and 2. on publication bias in reviews and meta-analyses for guidelines. For risk of bias, the involvement of the funding body in the study is checked as well as the direction of the effect. For publication bias, the exploration by the authors is evaluated, and any difference between industry-funded and non-funded studies in effect is checked. Guiding questions were proposed., Conclusion: The step-by-step approaches make the evaluation of the influence of the funding body more objective and transparent in our institutes. The developed approaches will also be brought forward to the Grading of Recommendations Assessment, Development and Evaluation working group., Competing Interests: Declaration of competing interest B.S., A.S., T.K., and S.H. are members of the Dutch GRADE Network and the GRADE Working Group., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs) 1,2 , conferring a predisposition to life-threatening COVID-19 pneumonia 3 . Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52 LOF /IκBδ GOF ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52 LOF /IκBδ LOF ) or gain-of-function of p52 (hereafter, p52 GOF /IκBδ LOF ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases., (© 2023. The Author(s).)

The overall disease burden of pediatric infection is high, with widely varying clinical outcomes including death. Among the most vulnerable children, those with inborn errors of immunity, reduced penetrance and variable expressivity are common but poorly understood. There are several genetic mechanisms that influence phenotypic variation in inborn errors of immunity, as well as a body of knowledge on environmental influences and specific pathogen triggers. Critically, recent advances are illuminating novel nuances for fundamental concepts on disease penetrance, as well as raising new areas of inquiry. The last few decades have seen the identification of almost 500 causes of inborn errors of immunity, as well as major advancements in our ability to characterize somatic events, the microbiome, and genotypes across large populations. The progress has not been linear, and yet, these developments have accumulated into an enhanced ability to diagnose and treat inborn errors of immunity, in some cases with precision therapy. Nonetheless, many questions remain regarding the genetic and environmental contributions to phenotypic variation both within and among families. The purpose of this review is to provide an updated summary of key concepts in genetic and environmental contributions to phenotypic variation within inborn errors of immunity, conceptualized as including dynamic, reciprocal interplay among factors unfolding across the key dimension of time. The associated findings, potential gaps, and implications for research are discussed in turn for each major influencing factor. The substantial challenge ahead will be to organize and integrate information in such a way that accommodates the heterogeneity within inborn errors of immunity to arrive at a more comprehensive and accurate understanding of how the immune system operates in health and disease. And, crucially, to translate this understanding into improved patient care for the millions at risk for serious infection and other immune-related morbidity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Similuk and Kuijpers.)

Background: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood., Methods: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children., Findings: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures., Conclusions: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis., Funding: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC., Competing Interests: Declaration of interests The authors declare that a patent application on the method described in this manuscript has been filed (2304229.4/GB/PRV, 23-03-2023)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease., (© 2023. Springer Nature Limited.)

Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections., Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39)., Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV., Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background: It is unclear which patients with multiple sclerosis (MS) are most susceptible for omicron breakthrough infections., Methods: We assessed omicron breakthrough infections in vaccinated patients with MS with and without disease-modifying therapies enrolled in an ongoing large prospective study. We longitudinally studied humoral responses after primary and booster vaccinations and breakthrough infections., Results: Omicron breakthrough infections were reported in 110/312 (36%) patients with MS, and in 105/110 (96%) infections were mild. Omicron breakthrough infections occurred more frequently in patients treated with anti-CD20 therapies and sphingosine-1 phosphate receptor (S1PR) modulators, patients with impaired humoral responses after primary immunisation (regardless of treatment) and patients without prior SARS-CoV-2 infections. After infection, antibody titres increased in patients on S1PR modulator treatment while anti-CD20 treated patients did not show an increase., Conclusions: SARS-COV-2 omicron breakthrough infections are more prevalent in patients with MS on anti-CD20 therapies and S1PR modulators compared with other patients with MS, which correlated with decreased humoral responses after vaccination. Humoral responses after infection were higher in S1PR modulator-treated patients in comparison to patients on anti-CD20 therapies, suggesting that immunological protection from contracting infection or repeated exposures may differ between these therapies., Competing Interests: Competing interests: JK reported speaking and consulting relationships with Biogen, Genzyme, Merck, Novartis, Roche, Sanofi and TEVA. Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi and TEVA. TR reports consulting fees from Novartis. No other disclosures were reported., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: We aimed to develop a checklist to aid guideline developers in determining which scientific or societal cause ("triggers") are relevant when considering to initiate a rapid recommendation procedure., Methods: We conducted a two-round modified Delphi procedure with a panel of Dutch guideline experts, clinicians, and patient representatives. A previously conducted systematic literature review and semistructured interviews with four science journalists were used to generate a list of potential items. This item list was submitted to the panel for discussion, reduction and refinement into a checklist., Results: Thirteen experts took part. Two questionnaires were completed in which participants scored an initial list of 64 items based on relevance. During two online meetings, the scores were discussed, irrelevant items were removed, and relevant items were reformulated into seven questions. The final "quickscan assessment of the need for a rapid recommendation" covers user perspective, scientific evidence, clinical relevance, clinical practice variation, applicability, quality of care and public health outcomes, and ethical/legal considerations., Conclusion: The quickscan aids guideline developers in systematically assessing whether a trigger expresses a valid need for developing a rapid recommendation. Future research could focus on the applicability and validity of the checklist within guideline development programs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability., Methods and Findings: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics., Conclusion: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Dewez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality., Design: Preplanned analysis in prospective cohort study., Setting: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom)., Patients: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission., Interventions: None., Measurements and Main Results: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures., Conclusions: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections., Competing Interests: Drs. Hagedoorn’s and Zenz’s institutions received funding from the European Union (EU). Dr. Boeddha received funding from GlaxoSmithKline. Drs. Kohlfuerst’s, Hazelzet’s, and Emonts’ institutions received funding from EU Project European Union Childhood Life-threatening Infectious Disease study (EUCLIDS). Dr. Kohlfuerst received support for article research from EU Project EUCLIDS. Drs. Carrol, van der Flier, and Herberg received support for article research from EU Horizon 2020. Dr. Hazelzet’s institution received funding from Erasmus Medical Centre. Dr. Zenz received support for article research from the EU. Dr. Driessen’s institution received funding from Merck and the Elizabeth von Freyburg Foundation. Dr. Emonts’ institution received funding from the EU, FP7, EU H2020 Personalized Risk assessment in Febrile illness to Optimize Real-life Management across the European Union (PERFORM), and EU H2020 Diagnosis and Management of Febrile Illness using RNA Personalised Molecular Signature Diagnosis (DIAMONDS). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Mutations in the ARPC1B isoform component of human actin-related protein 2/3 complex have been recently associated with an inborn error of immunity characterized by combined immunodeficiency, allergies, autoinflammation, and platelet abnormalities. Currently, indications on the management of this novel disease and information on its outcome are lacking. We report the first case series of 7 children with a homozygous mutation in ARPC1B gene who underwent allogeneic-HSCT (allo-HSCT). All patients presented an early clinical onset, characterized by recurrent infections, failure to thrive and gastrointestinal bleeding episodes complicated with neonatal hemorrhagic enteritis in 3 cases, and macrophage activating syndrome in 2. Allo-HSCT was performed at the median age of 1.83 years after a myeloablative conditioning regimen in all cases. Engraftment occurred in all patients with full donor chimerism in 6 out of 7. The clinical course after engraftment was uneventful in 3 out of 7 children; 2 patients developed a grade 1-2 acute graft-versus-host disease (GvHD), and 1 patient a grade 1 chronic-GvHD. JC virus-related progressive multifocal leukoencephalopathy was diagnosed in one patient 13 months after haploidentical-HSCT and successfully managed with donor-derived viral-specific T-cell infusion. Only one patient had a fatal outcome 3 months after HSCT because of sepsis, after veno-occlusive disease, and transplant-associated microangiopathy. At a median follow-up of 19 months (range 3-110), 6 out of 7 patients are alive and disease-free. The severity of the clinical phenotype at diagnosis and the high survival rate, with limited transplant-related morbidity, strongly support the indication to allo-HSCT for patients with this diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery., (© 2022. The Author(s).)

Objectives: To systematically review the efficacy of interventions for Menière's disease (MD) to report clinical implications of the results and to identify areas for future valuable research., Methods: In line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Abstracts (PRISMA-A) guideline, a systematic online database search was conducted in which MEDLINE (PubMed), Embase (Ovid) and CENTRAL (Cochrane Library) were searched until May 2021 in order to search for the efficacy of treatment was analysed in a systematic review. Systematic reviews (SRs) on treatments for MD were screened for eligible interventions. From these SRs, we included placebo randomised controlled trials (RCTs). A separate search was conducted to identify RCTs on treatment modalities that were systematically reviewed yet published after the conduction of these SRs. The primary outcome was control of vertigo as defined by the American guideline as published in 1995. The PRISMA-A and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to appraise and evaluate the certainty of evidence., Results: We found five SRs from which 19 RCTs were extracted. Five RCTs were added by the separate search resulting in a total of 25 RCTs (n=1248) which evaluated the efficacy of betahistine dihydrochloride, intratympanic injections with gentamicin or steroids, endolymphatic sac surgery and pressure pulse therapy. Evidence on the efficacy of interventions for patients with MD is generally of low certainty. Betahistine (48 mg per day and 144 mg per day) and positive pressure therapy probably do not reduce MD symptoms when compared with placebo. Intratympanic injection with gentamicin or steroids, or treatment with endolymphatic surgery may reduce symptoms in MD when compared with placebo., Conclusions: A definite effective and well-tolerated therapy for MD has yet to be discovered and information on the natural course of disease is one of the biggest flaws in current research., Prospero Registration Number: CRD4201502424., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Approximately 25% of the patients with a history of Kawasaki disease (KD) develop coronary artery pathology if left untreated, with coronary artery aneurysms (CAA) as an early hallmark. Depending on the severity of CAAs, these patients are at risk of myocardial ischemia, infarction and sudden death. In order to reduce cardiac complications it is crucial to accurately identify patients with coronary artery pathology by an integrated cardiovascular program, tailored to the severity of the existing coronary artery pathology., Methods: The development of this practical workflow for the cardiovascular assessment of KD patients involve expert opinions of pediatric cardiologists, infectious disease specialists and radiology experts with clinical experience in a tertiary KD reference center of more than 1000 KD patients. Literature was analyzed and an overview of the currently most used guidelines is given., Conclusions: We present a patient-specific step-by-step, integrated cardiovascular follow-up approach based on expert opinion of a multidisciplinary panel with expertise in KD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Stijn, Planken, Groenink, Blom, de Winter, Kuijpers and Kuipers.)

Background: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines., Objective: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist., Design: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group., Setting: International collaboration., Participants: A total of 119 professionals participated in the development process., Measurements: Participants' consensus on items in the checklist., Results: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience., Limitation: The RIGHT-Ad@pt checklist requires further validation in real-life use., Conclusion: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations., Primary Funding Source: None.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13., (© 2021. The Author(s).)

Given the increasing reports of well-defined bimetallic molecular complexes as potential anticancer agents in the last decades, along with the prevalence of platinum in anticancer therapy, we report here a detailed survey of bimetallic platinum and palladium complexes investigated as potential anticancer agents. Specifically, we will concentrate on the synthesis, characterisation and biological (anticancer) studies of a sub-class of these agents, namely homo and heterobimetallic complexes bearing a bridging phosphane ligand of the type: [L n M 1 (μ-R 2 P(CH 2 ) n PR 2 )M 2 L m ] (where M 1 is platinum or palladium, M 2 is any other transition metal, R = alkyl or aryl substituents, L n or L m are co-ligands, n = 1-6). We will review the in vitro and in vivo activities and any mechanistic anticancer studies of these complexes with a view of trying to delineate patterns in biological activity and structure-activity relationships (SAR). We do not include the review of bimetallic complexes in this class that have not undergone any anticancer testing, nor those that have been involved in other biological investigations unrelated to cancer studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host 'omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple 'omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of 'omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both 'omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both 'omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.

Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z- score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD. Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA. Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Stijn-Bringas Dimitriades, Planken, Kuipers and Kuijpers.)

Background: Kawasaki Disease (KD) is a pediatric vasculitis of which the pathogenesis is unclear. The hypothesis is that genetically pre-disposed children develop KD when they encounter a pathogen which remains most often unidentified or pathogen derived factors. Since age is a dominant factor, prior immune status in children could influence their reactivity and hence the acquisition of KD. We hypothesized that systemic immune responses early in life could protect against developing KD. With this study we tested whether the incidence of previous systemic cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection is lower in children with KD compared to healthy age-matched controls. Methods and Results: We compared 86 KD patients with an age-matched control group regarding CMV and EBV VCA IgG measurements (taken before or 9 months after IVIG treatment). We found that both CMV and EBV had an almost 2-fold lower seroprevalence in the KD population than in the control group. Conclusions: We suggest that an under-challenged immune system causes an altered immune reactivity which may affect the response to a pathological trigger causing KD in susceptible children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Stijn-Bringas Dimitriades, Slegers, Zaaijer and Kuijpers.)

Background: There are now over 140 tools/programs that can assist in developing systematic reviews or clinical practice guidelines (CPGs). It is currently unclear which tools are used by systematic reviewers and CPG developers, which development processes they are used for, and what facilitators or barriers to their use exist., Methods: To determine which tools are currently being used by systematic reviewers and CPG developers, an online survey was administered during July-August 2017. Guidelines International Network individual and organizational members were invited to participate. Survey questions focused on the nature and frequency of members' use of tools to support systematic review and CPG development., Results: The overall response rate was 34%. The largest number of respondents developed one to five guidelines a year (48%). GRADEpro GDT was the most popular tool (26% of respondents) followed by Dropbox (16%) and RevMan (14%). From the options provided, the reason most respondents (85%) used particular tools was 'to be more efficient'. Most users stated they would use the tool again (95%), and 95% would recommend it to other organizations. However, respondents reported that tool efficiency and facilitators such as data sharing functionality were offset by their availability and cost, issues with structured data fields (that did not allow customization), and other technical and usability factors (e.g., features, workflows)., Conclusion: The results of this survey provide a focus for discussing improvements in tools to meet the needs of systematic reviewers and CPG developers, and a basis from which to test the efficacy and appropriateness of various tools and platforms across a number of purposes and contexts.

Objective: The objective of this study was to provide guidance on the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine certainty in estimates of association between prognostic factors and future outcomes., Study Design and Setting: We developed our guidance through an iterative process that involved review of published systematic reviews and meta-analyses of prognostic factors, consultation with members, feedback, presentation, and discussion at the GRADE Working Group meetings., Results: For questions of prognosis, a body of observational evidence (potentially including patients enrolled in randomized controlled trials) begins as high certainty in the evidence. The five domains of GRADE for rating down certainty in the evidence, that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias, as well as the domains for rating up, also apply to estimates of associations between prognostic factors and outcomes. One should determine if their ratings do not consider (noncontextualized) or consider (contextualized) the clinical context as this will may result in variable judgments on certainty of the evidence., Conclusions: The same principles GRADE proposed for bodies of evidence addressing treatment and overall prognosis work well in assessing individual prognostic factors, both in noncontextualized and contextualized settings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Study Design and Setting: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants., Results: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively., Conclusions: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease., Methods: Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochrome b558 were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results., Results: The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carried CYBB variants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carried NCF1 variants, 4 (17.4%) carried CYBA variants, and 3 (13%) carried NCF2 variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG in CYBB (OMIM#300481) and a novel c.251&#95;263del13bp in CYBA (OMIM#608508) were also investigated., Conclusions: Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case with CYBB variant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious., (© 2020 S. Karger AG, Basel.)

Clinical Question: What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice., Current Practice: Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing., Recommendation: The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old)., How This Guideline Was Created: A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach., The Evidence: The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years' follow-up., Understanding the Recommendation: The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form and a detailed, contextualised description of all disclosures is reported in appendix 2 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any relevant financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. M Feller, M Snel, E Moutzouri, and N Rodondi participated in writing the systematic review that formed the evidence base for this guideline. JP Brito and N Singh Ospina wrote an editorial about the overuse of levothyroxine., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: It remains uncertain which diet is best for people with type 2 diabetes (T2D)., Objective: We compared the effects of dietary carbohydrate restriction with fat restriction on markers of metabolic syndrome and quality of life in people with T2D., Design: This systematic review of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) compares the effects of a low-carbohydrate [≤40% of energy (%)] diet with those of a low-fat (≤30%) diet over a period of ≥4 wk in patients with T2D. Two investigators independently selected studies, extracted data, and assessed risk of bias. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess the certainty of evidence. Pooled mean differences (MDs) and 95% CIs were calculated with the use of a random-effects model., Results: Thirty-three RCTs and 3 CCTs (n = 2161) were included. Glycated hemoglobin declined more in people who consumed low-carbohydrate food than in those who consumed low-fat food in the short term (MD: -1.38%; 95% CI: -2.64%, -0.11%; very-low-certainty evidence). At 1 y, the MD was reduced to -0.36% (95% CI: -0.58%, -0.14%; low-certainty evidence); at 2 y, the difference had disappeared. There is low to high (majority moderate) certainty for small improvements of unclear clinical importance in plasma glucose, triglycerides, and HDL concentrations favoring low-carbohydrate food at half of the prespecified time points. There was little to no difference in LDL concentration or any of the secondary outcomes (body weight, waist circumference, blood pressure, quality of life) in response to either of the diets (very-low- to high-certainty evidence)., Conclusions: Currently available data provide low- to moderate-certainty evidence that dietary carbohydrate restriction to a maximum of 40% yields slightly better metabolic control of uncertain clinical importance than reduction in fat to a maximum of 30% in people with T2D. This systematic review is registered at http://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?ID=CRD42017052467 as CRD42017052467.

Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a detailed description of all disclosures is reported in appendix 2 on bmj.com. No authors had relevant financial interests. They declared the following intellectual interests: Elke Hoendermis is co-author of national recommendations on PFO closure and stroke on behalf of the working group of the Netherlands Society of Cardiology. Fred Spencer has published systematic review and meta-analysis on this topic. No panel member had any other intellectual conflict to disclose. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions.

Objective: To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone., Design: Systematic review and network meta-analysis (NMA) supported by complementary external evidence., Data Sources: Medline, EMBASE and Cochrane CENTRAL., Study Selection: Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke., Review Methods: We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system., Results: Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): -87, 95% credible interval (CrI) -100 to -33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD -20, 95% CrI -27 to -2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD -71, 95% CrI -100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI -5 to +65, moderate certainty)., Conclusions: In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding., Prospero Registration Number: CRD42017081567., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations disclosure form, which asks about any possible financial, intellectual and professional conflicts of interest (available on request). To summarise, J-LM has received consulting honoraria from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GECKO and Servier. HM, RACS, TK, PV, TA and GHG are also panel members of the linked Rapid Recommendation guideline panel., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs. Epigenetic comparison with low/intermediate-risk APLs and AMLs revealed hrAPL-specific patterns of histone acetylation and DNA methylation, suggesting these could be further developed into markers for clinical identification. The epigenetic drug MC2884, a newly generated general HAT/EZH2 inhibitor, induces apoptosis of high-risk APL blasts and reshapes their epigenomes by targeting both active and repressive marks. Together, our analysis uncovers distinctive epigenome signatures of hrAPL patients, and provides proof of concept for use of epigenome profiling coupled to epigenetic drugs to 'personalize' precision medicine., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Hematopoietic differentiation of human induced pluripotent stem cells (iPSCs) provide opportunities not only for fundamental research and disease modelling/drug testing but also for large-scale production of blood effector cells for future clinical application. Although there are multiple ways to differentiate human iPSCs towards hematopoietic lineages, there is a need to develop reproducible and robust protocols. Here we introduce an efficient way to produce three major blood cell types using a standardized differentiation protocol that starts with a single hematopoietic initiation step. This system is feeder-free, avoids EB-formation, starts with a hematopoietic initiation step based on a novel single cell-derived iPSC colony differentiation and produces multi-potential progenitors within 8-10 days. Followed by lineage-specific growth factor supplementation these cells can be matured into well characterized erythroid, megakaryocytic and myeloid cells with high-purity, without transcription factor overexpression or any kind of pre-purification step. This standardized differentiation system provides a simple platform to produce specific blood cells in a reproducible manner for hematopoietic development studies, disease modelling, drug testing and the potential for future therapeutic applications., (Copyright © 2018. Published by Elsevier B.V.)

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver-specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Research investigating prognosis in musculoskeletal pain conditions has only been moderately successful in predicting which patients are unlikely to recover. Clinical decision making could potentially be improved by combining information taken at baseline and re-consultation., Methods: Data from four prospective clinical cohorts of adults presenting to UK and Dutch primary care with low-back or shoulder pain was analysed, assessing long-term disability at 6 or 12 months and including baseline and 4-6 week assessments of pain. Baseline versus short-term assessments of pain, and previously validated multivariable prediction models versus repeat assessment, were compared to assess predictive performance of long-term disability outcome. A hypothetical clinical scenario was explored which made efficient use of both baseline and repeated assessment to identify patients likely to have a poor prognosis and decide on further treatment., Results: Short-term repeat assessment of pain was better than short-term change or baseline score at predicting long-term disability improvement across all cohorts. Short-term repeat assessment of pain was only slightly more predictive of long-term recovery (c-statistics 0.78, 95% CI 0.74 to 0.83 and 0.75, 95% CI 0.69 to 0.82) than a multivariable baseline prognostic model in the two cohorts presenting such a model (c-statistics 0.71, 95% CI 0.67 to 0.76 and 0.72, 95% CI 0.66 to 0.78). Combining optimal prediction at baseline using a multivariable prognostic model with short-term repeat assessment of pain in those with uncertain prognosis in a hypothetical clinical scenario resulted in reduction in the number of patients with an uncertain probability of recovery, thereby reducing the instances where patients may be inappropriately referred or reassured., Conclusions: Incorporating short-term repeat assessment of pain into prognostic models could potentially optimise the clinical usefulness of prognostic information.