Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases

Introduction: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. Objective: We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients. Methods: A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000–2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]). Results: We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57–4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08–3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78–49.54) for cotrimoxazole (i.e. sulphamethoxa

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

Hybrid electronic–photonic sensors on a fibre tip

Most sensors rely on a change in an electrical parameter to the measurand of interest. Their direct readout via an electrical wire and an electronic circuit is, in principle, technically simple, but it is subject to electromagnetic interference, preventing its application in several industrial environments. Fibre-optic sensors can overcome these limitations because the sensing region and readout region can be spaced apart, sometimes by kilometres. However, fibre-optic sensing typically requires complex interrogation equipment due to the extremely high wavelength accuracy that is required. Here we combine the sensitivity and flexibility of electronic sensors with the advantages of optical readout, by demonstrating a hybrid electronic–photonic sensor integrated on the tip of a fibre. The sensor is based on an electro-optical nanophotonic structure that uses the strong co-localization of static and electromagnetic fields to simultaneously achieve a voltage-to-wavelength transduction and a modulation of reflectance. We demonstrate the possibility of reading the current–voltage characteristics of the electro-optic diode through the fibre and therefore its changes due to the environment. As a proof of concept, we show the application of this method to cryogenic temperature sensing. This approach allows fibre-optic sensing to take advantage of the vast toolbox of electrical sensing modalities for many different measurands.</p

Abobotulinumtoxina and rehabilitation vs rehabilitation alone in post-stroke spasticity: A cost-utility analysis

Objective: To investigate costs and quality-adjusted life years of rehabilitation combined with abobotulinumtoxinA (aboBoNT-A) (rehab/aboBoNT-A) vs rehabilitation alone (rehab) in post-stroke spasticity in Italy. Design: Based on both Italian National Health Service and societal perspectives, a 2-year cost-utility analysis model was performed. Subject/patients: The cost-utility analysis model considered hypothetical patients. Methods: The cost-utility analysis model was populated with data concerning demographics, disease severity, healthcare and non-healthcare resource consumption. Data were collected via a questionnaire administered to 3 highly experienced Italian physiatrists (864 out of 930 post-stroke spasticity patients on rehab/aboBoNT-A in total). Costs are expressed in Euro (\u20ac) based on the year 2018. Results: The cost to society (rounded to the nearest whole \u20ac) was \u20ac22,959 (rehab/aboBoNT-A) vs \u20ac11,866 (rehab). Italian National Health Servicefunded cost was \u20ac7,593 (rehab/aboBoNT-A) vs \u20ac1,793 (rehab). Over a period of 2 years rehab/aboBoNT-A outperforms rehab in terms of qualityadjusted life years gained (1.620 vs 1.150). The incremental cost-utility ratio was \u20ac12,341 (Italian National Health Service viewpoint) and \u20ac23,601 (societal viewpoint). Sensitivity analyses confirmed the robustness of the baseline results. Conclusion: Despite some limitations, the higher number of quality-adjusted life years gained vs rehab and the high probability of reaching a cost-utility ratio lower than the Italian informal acceptability range (\u20ac25,000-40,000) make rehab/aboBoNT-A a cost-effective healthcare programme for treating patients with post-stroke spasticity in Italy

Rehabilitation Procedures in the Management of Parkinson’s Disease

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Assessment of pediatric asthma drug use in three European countries; a TEDDY study.

Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 0-18 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. ß2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, ß2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for ß2-mimetics (the UK highest). Off-label use was low, and most pronounced for ß2-mimetics in children <18 months (IT) and combined ß2-mimetics + anticholinergics in children <6 years (NL). CONCLUSION: This study shows that among all asthma drugs, ß2-mimetics and inhaled steroids are most often used, also in children without asthma, and with large variability between countries. Linking multi-country databases allows us to study country specific pediatric drug use in a systematic manner without being hampered by methodological differences. This study underlines the potency of healthcare databases in rapidly providing data on pediatric drug use and possibly safety

Burden of acute otitis media in primary care pediatrics in Italy: A secondary data analysis from the Pedianet database

Background: The incidence of acute otitis media (AOM) vary from country to country. Geographical variations together with differences in study designs, reporting and settings play a role. We assessed the incidence of AOM in Italian children seen by primary care paediatricians (PCPs), and described the methods used to diagnose the disease.Methods: This secondary data analysis from the Pedianet database considered children aged 0 - 6 years between 01/2003 and 12/2007. The AOM episodes were identified and validated by means of patient diaries. Incidence rates/100 person-years (PY) were calculated for total AOM and for single or recurrent AOM.Results: The 92,373 children (52.1% males) were followed up for a total of 227,361 PY: 23,039 (24.9%) presented 38,241 episodes of AOM (94.6% single episodes and 5.4% recurrent episodes). The total incidence rate of AOM in the 5-year period was 16.8 episodes per 100 PY (95% CI: 16.7-16.9), including single AOM (15.9 episodes per 100 PY; 95% CI: 15.7-16.1) and recurrent AOM (0.9 episodes per 100 PY; 95% CI: 0.9-0.9). There was a slight and continuously negative trend decrease over time (annual percent change -4.6%; 95%CI: -5.3, -3.9%). The AOM incidence rate varied with age, peaking in children aged 3 to 4 years (22.2 episodes per 100 PY; 95% CI 21.8-22.7). The vast majority of the AOM episodes (36,842/38,241, 96.3%) were diagnosed using a static otoscope; a pneumatic otoscope was used in only 3.7%.Conclusions: Our data fill a gap in our knowledge of the incidence of AOM in Italy, and indicate that AOM represents a considerable burden for the Italian PCP system. Educational programmes concerning the diagnosis of AOM are needed, as are further studies to monitor the incidence in relation to the introduction of wider pneumococcal conjugate vaccines

Modular construction of mammalian gene circuits using TALE transcriptional repressors

An important goal of synthetic biology is the rational design and predictable implementation of synthetic gene circuits using standardized and interchangeable parts. However, engineering of complex circuits in mammalian cells is currently limited by the availability of well-characterized and orthogonal transcriptional repressors. Here, we introduce a library of 26 reversible transcription activator–like effector repressors (TALERs) that bind newly designed hybrid promoters and exert transcriptional repression through steric hindrance of key transcriptional initiation elements. We demonstrate that using the input-output transfer curves of our TALERs enables accurate prediction of the behavior of modularly assembled TALER cascade and switch circuits. We also show that TALER switches using feedback regulation exhibit improved accuracy for microRNA-based HeLa cancer cell classification versus HEK293 cells. Our TALER library is a valuable toolkit for modular engineering of synthetic circuits, enabling programmable manipulation of mammalian cells and helping elucidate design principles of coupled transcriptional and microRNA-mediated post-transcriptional regulation.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50GM098792)National Institutes of Health (U.S.) (Grant 1R01CA173712-01

Diagnostic nerve block in prediction of outcome of botulinum toxin treatment for spastic equinovarus foot after stroke: A retrospective observational study

Objective: To evaluate the role of diagnostic nerve block in predicting the outcome of subsequent botulinum toxin type A treatment for spastic equinovarus foot due to chronic stroke. Design: Retrospective observational study. Patients: Fifty chronic stroke patients with spastic equinovarus foot. Methods: Each patient was given diagnostic tibial nerve block (lidocaine 2% perineural injection) assessment followed by botulinum toxin type A inoculation into the same muscles as had been targeted by the nerve block. All patients were evaluated before diagnostic nerve block, after the nerve block, and 4 weeks after botulinum toxin injection. Outcomes were ankle dorsiflexion passive range of motion of the affected side, and calf muscle spasticity, measured with the modified Ashworth scale and the Tardieu Scale. Results: Significant improvements were measured after diagnostic nerve block and botulinum toxin injection compared with the baseline condition. Diagnostic nerve block led to significantly greater improvements in all outcomes than botulinum toxin injection. Conclusion: This study confirmed diagnostic nerve block as a valuable screening tool in deciding whether to treat spastic equinovarus with botulinum toxin. However, the results support the evidence that diagnostic nerve block results in a greater reduction in muscle overactivity than does botulinum toxin type A in patients with spastic equinovarus due to stroke