Impact of guidelines implementation on empiric antibiotic treatment for pediatric uncomplicated osteomyelitis and septic arthritis over a ten-year period: Results of the ELECTRIC study (ostEomyeLitis and sEptiC arThritis tReatment in children)

Background: Due to the growing evidence of the efficacy of intravenous (IV) cefazolin with an early switch to oral cefalexin in uncomplicated pediatric osteomyelitis (OM) and septic arthritis (SA) in children, we changed our guidelines for empiric antibiotic therapy in these conditions. This study aims at evaluating the impact of the guidelines' implementation in reducing broad-spectrum antibiotic prescriptions, duration of IV antibiotic treatment and hospital stay, treatment failure and recurrence. Materials and methods: This is a retrospective, observational, quasi-experimental study. The four years pre-intervention were compared to the six years, ten months post-intervention (January 2012, through December 2015; January 2016, through October 31st, 2022). All patients aged 3 months to 18 years with OM or SA were evaluated for inclusion. Each population was divided into three groups: pre-intervention, post-intervention not following the guidelines, and post-intervention following the guidelines. Differences in antibiotic prescriptions such as Days of Therapy (DOT), activity spectrum and Length of Therapy (LOT), length of hospital stay (LOS), broad-spectrum antibiotics duration (bsDOT), treatment failure and relapse at six months were analyzed as outcomes. Results: Of 87 included patients, 48 were diagnosed with OM (8 pre-intervention, 9 post-intervention not following the guidelines and 31 post-intervention following the guidelines) and 39 with SA (9 pre-intervention, 12 post-intervention not following the guidelines and 18 post-intervention following the guidelines). In OM patients, IV DOT, DOT/LOT ratio, and bsDOT were significantly lower in the guidelines group, with also the lowest proportion of patients discharged on IV treatment. Notably, significantly fewer cases required surgery in the post-intervention groups. Considering SA, LOS, IV DOT, DOT/LOT ratio, and bsDOT were significantly lower in the guidelines group. The treatment failure rate was comparable among all groups for both OM and SA. There were no relapse cases. The overall adherence was between 72 and 100%. Conclusions: The implementation of guidelines was effective in decreasing the extensive use of broad-spectrum antibiotics and combination therapy for both OM and SA. Our results show the applicability, safety, and efficacy of a narrow-spectrum IV empirical antibiotic regimen with cefazolin, followed by oral monotherapy with first/second-generation cephalosporins, which was non-inferior to broad-spectrum regimens

Comparative study showed that children faced a 78% higher risk of new-onset conditions after they had COVID-19

Aim: Children have largely been unaffected by severe COVID-19 compared to adults, but data suggest that they may have experienced new conditions after developing the disease. We compared outcomes in children who had experienced COVID-19 and healthy controls. / Methods: A retrospective nested cohort study assessed the incidence rate of new-onset conditions after COVID-19 in children aged 0–14 years. Data were retrieved from an Italian paediatric primary care database linked to Veneto Region registries. Exposed children with a positive nasopharyngeal swab were matched 1:1 with unexposed children who had tested negative. Conditional Cox regression was fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the exposure and outcome associations after adjusting for covariates. / Results: We compared 1656 exposed and 1656 unexposed children from 1 February 2020 to 30 November 2021. The overall excess risk for new-onset conditions after COVID-19 was 78% higher in the exposed than unexposed children. We found significantly higher risks for some new conditions in exposed children, including mental health issues (aHR 1.8, 95% CI 1.1–3.0) and neurological problems (aHR 2.4, 95% CI 1.4–4.1). / Conclusion: Exposed children had a 78% higher risk of developing new conditions of interest after COVID-19 than unexposed children

Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders

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Modelling the Health and Economic Impacts of Population-Wide Testing, Contact Tracing and Isolation (PTTI) Strategies for COVID-19 in the UK

Background: The COVID-19 epidemic in the UK has resulted in over 280,000 reported cases and over 40,000 deaths as of 5th June 2020. In the context of a slower increase in reported cases and deaths associated with COVID-19 over the last few weeks compared to earlier in the epidemic, the UK is starting to relax the physical restrictions (‘lockdown’) that have been imposed since 23 March 2020. This has been accompanied by the announcement of a strategy to test people for infection, trace contacts of those tested positive, and isolate positive diagnoses. While such policies are expected to be impactful, there is no conclusive evidence of which approach to this is likely to achieve the most appropriate balance between benefits and costs. This study combines mathematical and economic modelling to estimate the impact, costs, feasibility, and health and economic effects of different strategies. / Methods: We provide detailed description, impact, costing, and feasibility assessment of population-scale testing, tracing, and isolation strategies (PTTI). We estimate the impact of different PTTI strategies with a deterministic mathematical model for SARS-CoV-2 transmission that accurately captures tracing and isolation of contacts of individuals exposed, infectious, and diagnosed with the virus. We combine this with an economic model to project the mortality, intensive care, hospital, and non-hospital case outcomes, costs to the UK National Health Service, reduction in GDP, and intervention costs of each strategy. Model parameters are derived from publicly available data, and the model is calibrated to reported deaths associated with COVID-19. We modelled 31 scenarios in total (Panel 2). The first 18 comprised nine with ‘triggers’ (labelled with the -Trig suffix) for subsequent lockdown periods (>40,000 new infections per day) and lockdown releases (<10,000 new infections per day), and nine corresponding scenarios without triggers, namely: no large-scale PTTI (scenario 1); scale-up of PTTI to testing the whole population every week, with May–July 2020 lockdown release (scenario 2b), or delayed lockdown release until scale-up complete on 31 August 2020 (scenario 2a); these two scenarios with mandatory use of face coverings (scenarios 3a and 3b); and scenarios 2a, 2b, 3a, 3b replacing untargeted PTTI with testing of symptomatic people only (scenarios 4a, 4b, 4c, 4d). The final 13 scenarios looked at: whole population weekly testing to suppress the epidemic with lower tracing success (scenarios 3b-Trig00, 3b-Trig10, 3b-Trig20, 3b-Trig30) and switched to targeted testing after two months when it may suppress the epidemic (scenarios 3b-Trig00-2mo and 3b-Trig30-2mo), and targeted testing with lower tracing success (scenarios 4d-Trig10, 4dTrig20, 4d-Trig30, 4d-Trig40, 4d-Trig50, 4d-Trig60, 4d-Trig70). / Findings: Given that physical distancing measures have already been relaxed in the UK, scenario 4d-Trig (targeted testing of symptomatic people only, with a mandatory face coverings policy and subsequent lockdown triggered to enable PTTI to suppress the epidemic), is a strategy that will result in the fewest deaths (~52,000) and has the lowest intervention costs (~£8bn). The additional lockdown results in total reduction in GDP of ~£503bn, less than half the cost to the economy of subsequent lockdowns triggered in a scenario without PTTI (scenario 1-Trig, ~£1180bn reduction in GDP, ~105,000 deaths). In summer months, with lower cold and flu prevalence, approximately 75,000 symptomatic people per day need to be tested for this strategy to work, assuming 64% of their contacts are effectively traced (~80% traced with 80% success) within the infectious period (most within the first two days and nearly all by seven days) and all are isolated – including those without any symptoms – for 14 days. Untargeted testing of everyone every week, if it were feasible, may work without tracing, but at a higher cost (scenario 3b-Trig00). This cost could be reduced by switching to targeted testing after the epidemic is suppressed (scenario 3b-Trig30-2mo), though we note the epidemic could be suppressed with targeted testing itself providing tracing and isolation has at least a 32% success rate (scenario 4dTrig40). / Interpretation: PTTI strategies to suppress the COVID-19 epidemic within the context of a relaxation of lockdown will necessitate subsequent lockdowns to keep the epidemic suppressed during PTTI scale-up. Targeted testing of symptomatic people only can suppress the epidemic if accompanied by mandated use of face coverings. The feasibility of PTTI depends on sufficient capacity, capabilities, infrastructure and integrated systems to deliver it. The political and public acceptability of alternative scenarios for subsequent lockdowns needs to take account of crucial implications for employment, personal and national debt, education, population mental health and non-COVID-19 disease. Our model is able to incorporate additional scenarios as the situation evolves

DOP011 A genome wide association study identifying association of the MHC region with 5-aminosalicylate (5-ASA) induced nephrotoxicity in inflammatory bowel disease

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Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Metallothionein genes: no association with Crohn's disease in a New Zealand population

Metallothioneins (MTs) are excellent candidate genes for Inflammatory Bowel Disease (IBD) and have previously been shown to have altered expression in both animal and human studies of IBD. This is the first study to examine genetic variants within the MT genes and aims to determine whether such genetic variants have an important role in this disease. 28 tag SNPs in genes MT1 (subtypes A, B, E, F, G, H, M, X), MT2, MT3 and MT4 were selected for genotyping in a well-characterized New Zealand dataset consisting of 406 patients with Crohn's Disease and 638 controls. We did not find any evidence of association for MT genetic variation with CD. The lack of association indicates that genetic variants in the MT genes do not play a significant role in predisposing to CD in the New Zealand population

Identification of HLA-DRPheβ47 as the susceptibility marker of hypersensitivity to beryllium in individuals lacking the berylliosis-associated supratypic marker HLA-DPGluβ69

BACKGROUND: Susceptibility to beryllium (Be)-hypersensitivity (BH) has been associated with HLA-DP alleles carrying a glutamate at position 69 of the HLA-DP β-chain (HLA-DPGlu69) and with several HLA-DP, -DQ and -DR alleles and polymorphisms. However, no genetic associations have been found between BH affected subjects not carrying the HLA-DPGlu69 susceptibility marker. METHODS: In this report, we re-evaluated an already described patient populations after 7 years of follow-up including new 29 identified BH subjects. An overall population 36 berylliosis patients and 38 Be-sensitization without lung granulomas and 86 Be-exposed controls was analysed to assess the role of the individual HLA-class II polymorphisms associated with BH-susceptibility in HLA-DPGlu69 negative subjects by univariate and multivariate analysis. RESULTS: As previously observed in this population the HLA-DPGlu69 markers was present in higher frequency in berylliosis patients (31 out of 36, 86%) than in Be-sensitized (21 out of 38, 55%, p = 0.008 vs berylliosis) and 41 out of 86 (48%, p < 0.0001 vs berylliosis, p = 0.55 vs Be-sensitized) Be-exposed controls. However, 22 subjects presenting BH did not carry the HLA-DPGlu69 marker. We thus evaluated the contribution of all the HLA-DR, -DP and -DQ polymorphisms in determining BH susceptibility in this subgroup of HLA-Glu69 subjects. In HLA-DPGlu69-negatives a significant association with BH was found for the HLA-DQLeu26, for the HLA-DRB1 locus residues Ser13, Tyr26, His32, Asn37, Phe47 and Arg74 and for the HLA-DRB3 locus clusterized residues Arg11, Tyr26, Asp28, Leu38, Ser60 and Arg74. HLA-DRPhe47 (OR 2.956, p < 0.05) resulting independently associated with BH. Further, Be-stimulated T-cell proliferation in the HLA-DPGlu69-negative subjects (all carrying HLA-DRPhe47) was inhibited by the anti-HLA-DR antibody (range 70–92% inhibition) significantly more than by the anti-HLA-DP antibody (range: 6–29%; p < 0.02 compared to anti-HLA-DR) while it was not affected by the anti-HLA-DQ antibody. CONCLUSION: We conclude that HLA-DPGlu69 is the primary marker of Be-hypersensitivity and HLA-DRPhe47 is associated with BH in Glu69-negative subjects, likely playing a role in Be-presentation and sensitization