Incidence, antimicrobial prescribing practice and associated healthcare costs of paediatric otorrhoea in primary care in the UK: A longitudinal population study.

Background Paediatric otorrhoea (PO) is a symptom-based diagnosis encompassing acute and chronic ear infections which cause otorrhoea in children and young people (CYP). Aim To understand the burden of PO on primary care services. Design and Setting A longitudinal population study in UK primary care. Methods Data from the Clinical Practice Research Datalink (CPRD Aurum), January 2005 to December 2019, was analysed. CYP under 17 years of age with otorrhoea were included. Standardised annual incidence and presentation rates were estimated. Poisson regression modelling was used to determine risk ratios comparing sex, age and IMD. A probabilistic simulation scaled-up estimates for the UK population. Results The cohort included 6,605,193 CYP, observed over 32,942,594 person-years. There were 80,454 incident cases and 106,318 presentations of PO during the 15-year period, equating to standardised annual incidence and presentation rates per 1000 patient-years of 2.42 (95% CI: 2.40-2.44) and 3.15 (3.13-3.17) respectively. In the UK this equates to 41,141 primary care appointments per year. Incidence was higher in males, those aged 0-2 years, and those living in the least deprived quintile. Treatment involved oral antibiotics (57.1%), no prescription (28.1%), topical antibiotics (9.7%), or combination (4.9%). The cost to NHS primary care is estimated at £1.97 million per year. Conclusions This is the first longitudinal population-based study investigating PO which demonstrates the burden on primary care. Antimicrobial prescribing predominantly follows NICE guidelines using oral amoxicillin. Aminoglycosides are the most frequently prescribed topical antibiotic despite the concern of ototoxicity.

Photogeneration of α-Bimetalloid Radicals via Selective Activation of Multifunctional C1 Units.

Light-driven strategies that enable the chemoselective activation of a specific bond in multifunctional systems are comparatively underexplored in comparison to transition-metal-based technologies, yet desirable when considering the controlled exploration of chemical space. With the current drive to discover next-generation therapeutics, reaction design that enables the strategic incorporation of an sp3 carbon center, containing multiple synthetic handles for the subsequent exploration of chemical space would be highly enabling. Here, we describe the photoactivation of ambiphilic C1 units to generate α-bimetalloid radicals using only a Lewis base and light source to directly activate the C-I bond. Interception of these transient radicals with various SOMOphiles enables the rapid synthesis of organic scaffolds containing synthetic handles (B, Si, and Ge) for subsequent orthogonal activation. In-depth theoretical and mechanistic studies reveal the prominent role of 2,6-lutidine in forming a photoactive charge transfer complex and in stabilizing in situ generated iodine radicals, as well as the influential role of the boron p-orbital in the activation/weakening of the C-I bond. This simple and efficient methodology enabled expedient access to functionalized 3D frameworks that can be further derivatized using available technologies for C-B and C-Si bond activation.

Risk factors associated with the development of chronic suppurative otitis media in children: Systematic review and meta-analysis.

OBJECTIVES: Chronic suppurative otitis media (CSOM) is defined as persistent discharge through a tympanic membrane perforation for greater than 2 weeks. It is associated with a significant disease burden, including hearing loss, and reducing its incidence could significantly improve short- and long-term health. We aimed to identify risk factors associated with the development of CSOM in children. DESIGN AND SETTING: Systematic review and meta-analysis of studies set in community, primary and secondary care settings, identified from Medline, Embase and Cochrane databases from 2000 to 2022. PARTICIPANTS: Children 16 years old and below. MAIN OUTCOME MEASURES: Clinical diagnosis of CSOM. RESULTS: In total, 739 papers were screened, with 12 deemed eligible for inclusion in the systematic review, of which, 10 were included in the meta-analysis. Risk factors examined included perinatal, patient, dietary, environmental and parental factors. Meta-analysis results indicate that atopy (RR = 1.18, 95% CI [1.01-1.37], p = .04, 2 studies); and birth weight <2500 g (RR = 1.79 [1.27-2.50], p < .01, 2 studies) are associated with an increased risk of CSOM development. Factors not associated were male sex (RR = 0.96 [0.82-1.13], p = .62, 8 studies); exposure to passive smoking (RR = 1.27 [0.81-2.01], p = .30, 3 studies); and parental history of otitis media (RR = 1.14 [0.59-2.20], p = .69, 2 studies). CONCLUSION: Optimal management of risk factors associated with CSOM development will help reduce the burden of disease and prevent disease progression or recurrence. The current quality of evidence in the literature is variable and heterogeneous. Future studies should aim to use standardised classification systems to define risk factors to allow meta-analysis.

Outcome measures for use in trials of paediatric otorrhoea: A systematic review.

INTRODUCTION: Paediatric otorrhoea (PO) describes a middle ear infection that results in a perforation of the tympanic membrane and ear discharge, in children and young people (CYP). Prolonged infection may be associated with hearing loss and developmental delay. The current management of paediatric otorrhoea is variable, including non-invasive treatments (conservative, oral antibiotics, topical antibiotics) and surgery, reflecting the lack of a sufficiently strong evidence base. Outcome reporting is fundamental to producing reliable and meaningful evidence to inform best practice. OBJECTIVES: Primary objective: to determine which outcome measures are currently used to evaluate treatment success in studies of non-surgical treatments for paediatric otorrhoea. SECONDARY OBJECTIVES: to identify outcome measurement instruments used in the literature and assess their applicability for use in clinical trials of PO. METHODS: This systematic review was registered with PROSPERO (CRD42023407976). Database searches of EMBASE, MEDLINE and Cochrane was performed on June 6, 2023, covering from Jan 1995 to May 2023. Randomised controlled trials or study protocols involving CYP with PO were included following PRISMA guidelines. Risk of bias was assessed with Cochrane's tool. RESULTS: Of the 377 papers identified, six were included in the systematic review. The primary outcome of five of the studies related to otorrhoea cessation; both time to cessation and proportion recovered at various time points were used as measures. Two measurement instruments were identified: Otitis Media-6 Questionnaire and the Institute for Medical Technology Assessment Productivity Cost Questionnaire. Both were shown to be applicable measurement instruments when used in clinical trials of PO. CONCLUSIONS: To promote homogeneity and facilitate meaningful comparison and combination of studies, we propose that time to cessation of otorrhoea from onset of otorrhoea should be used as the primary outcome in future studies. Further research is needed to establish if this is the most important outcome to children and their caregivers.

Synthetic biology identifies the minimal gene set required for paclitaxel biosynthesis in a plant chassis.

The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel from natural sources is limited. However, missing knowledge about the genes involved in several specific metabolic steps of paclitaxel biosynthesis has rendered it difficult to engineer the full pathway. In this study, we used a combination of transcriptomics, cell biology, metabolomics, and pathway reconstitution to identify the complete gene set required for the heterologous production of paclitaxel. We identified the missing steps from the current model of paclitaxel biosynthesis and confirmed the activity of most of the missing enzymes via heterologous expression in Nicotiana benthamiana. Notably, we identified a new C4ß-C20 epoxidase that could overcome the first bottleneck of metabolic engineering. We used both previously characterized and newly identified oxomutases/epoxidases, taxane 1ß-hydroxylase, taxane 9α-hydroxylase, taxane 9α-dioxygenase, and phenylalanine-CoA ligase, to successfully biosynthesize the key intermediate baccatin III and to convert baccatin III into paclitaxel in N. benthamiana. In combination, these approaches establish a metabolic route to taxoid biosynthesis and provide insights into the unique chemistry that plants use to generate complex bioactive metabolites.

Protocol for the Paediatric Otorrhoea Study (POSt): a multi-methods study to understand the burden of paediatric otorrhoea in the UK.

INTRODUCTION: Paediatric otorrhoea (PO) refers to the leakage of fluid through a perforation in the ear drum, resulting from an infection of the middle ear of a child or young person (CYP). PO frequently results in hearing loss which may lead to developmental delay, restricted communication and reduced educational attainment.Epidemiological information for PO is largely derived from low-income countries. The aim of this study will be to establish the incidence of PO within the UK and to understand the impact of PO on CYP and their families' everyday lives. It will build the foundations for a randomised controlled trial investigating the best antibiotic treatment for PO. METHODS AND ANALYSIS: The study will consist of two work packages. (1) Data from the Clinical Practice Research Datalink (CPRD), January 2005 to July 2021, will be used to determine the incidence of patient presentations with PO to primary care in the UK. It will also explore the current antimicrobial prescribing practice for PO in primary care. (2) Thirty semi-structured interviews will be conducted from 13 July to 31 October 2023 with CYP and their parents/carers to help identify the impact of PO on everyday life, the patient journey and how service users define treatment success. Three medical professional focus groups will be used to understand the current management practice, how treatment success is measured and acceptability to randomise patients. Thematic analysis will be used. ETHICS AND DISSEMINATION: The Health Research Authority, The Health and Social Care Research Ethics Committee (23/NI/0082) and the CPRD's research data governance panel (22_002508) reviewed this study. Results will be disseminated at medical conferences, in peer-reviewed journals and via social media. The study will cocreate a webpage on healthtalk.org, with the Dipex Charity, about PO to ensure members of the public can learn more about the condition. TRIAL REGISTRATION NUMBER: ISRCTN46071200.

Direct Light-Enabled Access to α-Boryl Radicals: Application in the Stereodivergent Synthesis of Allyl Boronic Esters.

Operationally simple strategies to assemble boron containing organic frameworks are highly enabling in organic synthesis. While conventional retrosynthetic logic has engendered many platforms focusing on the direct formation of C-B bonds, α-boryl radicals have recently reemerged as versatile open-shell alternatives to access organoborons via adjacent C-C bond formation. Direct light-enabled α-activation is currently contingent on photo- or transition metal-catalysis activation to efficiently generate radical species. Here, we disclose a facile activation of α-halo boronic esters using only visible light and a simple Lewis base to enable homolytic scission. Intermolecular addition to styrenes facilitates the rapid construction of highly versatile E-allylic boronic esters. The simplicity of activation permits the strategic merger of this construct with selective energy transfer catalysis to enable the complimentary stereodivergent synthesis of Z-allylic boronic esters.

Gut microbiota maturity mediates the protective effect of siblings on food allergy.

BACKGROUND: The mechanisms underlying the protective effect of older siblings on allergic disease remain unclear but may relate to the infant gut microbiota. OBJECTIVE: We sought to investigate whether having older siblings decreases the risk of IgE-mediated food allergy by accelerating the maturation of the infant gut microbiota. METHODS: In a birth cohort assembled using an unselected antenatal sampling frame (n = 1074), fecal samples were collected at 1 month, 6 months, and 1 year, and food allergy status at 1 year was determined by skin prick test and in-hospital food challenge. We used 16S rRNA gene amplicon sequencing to derive amplicon sequence variants. Among a random subcohort (n = 323), microbiota-by-age z scores at each time point were calculated using fecal amplicon sequence variants to represent the gut microbiota maturation over the first year of life. RESULTS: A greater number of siblings was associated with a higher microbiota-by-age z score at age 1 year (ß  = 0.15 per an additional sibling; 95% CI, 0.05-0.24; P = .003), which was in turn associated with decreased odds of food allergy (odds ratio, 0.45; 95% CI, 0.33-0.61; P < .001). Microbiota-by-age z scores mediated 63% of the protective effect of siblings. Analogous associations were not observed at younger ages. CONCLUSIONS: The protective effect of older siblings on the risk of developing IgE-mediated food allergy during infancy is substantially mediated by advanced maturation of the gut microbiota at age 1 year.

Value assignment and uncertainty evaluation for anion and single-element reference solutions incorporating historical information.

The National Institute of Standards and Technology, which is the national metrology institute of the USA, assigns certified values to the mass fractions of individual elements in single-element solutions, and to the mass fractions of anions in anion solutions, based on gravimetric preparations and instrumental methods of analysis. The instrumental method currently is high-performance inductively coupled plasma optical emission spectroscopy for the single-element solutions, and ion chromatography for the anion solutions. The uncertainty associated with each certified value comprises method-specific components, a component reflecting potential long-term instability that may affect the certified mass fraction during the useful lifetime of the solutions, and a component from between-method differences. Lately, the latter has been evaluated based only on the measurement results for the reference material being certified. The new procedure described in this contribution blends historical information about between-method differences for similar solutions produced previously, with the between-method difference observed when a new material is characterized. This blending procedure is justified because, with only rare exceptions, the same preparation and measurement methods have been used historically: in the course of almost 40 years for the preparation methods, and of 20 years for the instrumental methods. Also, the certified values of mass fraction, and the associated uncertainties, have been very similar, and the chemistry of the solutions also is closely comparable within each series of materials. If the new procedure will be applied to future SRM lots of single-element or anion solutions routinely, then it is expected that it will yield relative expanded uncertainties that are about 20 % smaller than the procedure for uncertainty evaluation currently in use, and that it will do so for the large majority of the solutions. However, more consequential than any reduction in uncertainty, is the improvement in the quality of the uncertainty evaluations that derives from incorporating the rich historical information about between-method differences and about the stability of the solutions over their expected lifetimes. The particular values listed for several existing SRMs are given merely as retrospective illustrations of the application of the new method, not to suggest that the certified values or their associated uncertainties should be revised.

The Impact of Boron Hybridisation on Photocatalytic Processes.

Recently the fruitful merger of organoboron chemistry and photocatalysis has come to the forefront of organic synthesis, resulting in the development of new technologies to access complex (non)borylated frameworks. Central to the success of this combination is control of boron hybridisation. Contingent on the photoactivation mode, boron as its neutral planar form or tetrahedral boronate can be used to regulate reactivity. This Minireview highlights the current state of the art in photocatalytic processes utilising organoboron compounds, paying particular attention to the role of boron hybridisation for the target transformation.

Advances in the E → Z Isomerization of Alkenes Using Small Molecule Photocatalysts.

Geometrical E → Z alkene isomerization is intimately entwined in the historical fabric of organic photochemistry and is enjoying a renaissance (Roth et al. Angew. Chem., Int. Ed. Engl. 1989 28, 1193-1207). This is a consequence of the fundamental stereochemical importance of Z-alkenes, juxtaposed with frustrations in thermal reactivity that are rooted in microscopic reversibility. Accessing excited state reactivity paradigms allow this latter obstacle to be circumnavigated by exploiting subtle differences in the photophysical behavior of the substrate and product chromophores: this provides a molecular basis for directionality. While direct irradiation is operationally simple, photosensitization via selective energy transfer enables augmentation of the alkene repertoire to include substrates that are not directly excited by photons. Through sustained innovation, an impressive portfolio of tailored small molecule catalysts with a range of triplet energies are now widely available to facilitate contra-thermodynamic and thermo-neutral isomerization reactions to generate Z-alkene fragments. This review is intended to serve as a practical guide covering the geometric isomerization of alkenes enabled by energy transfer catalysis from 2000 to 2020, and as a logical sequel to the excellent treatment by Dugave and Demange (Chem. Rev. 2003 103, 2475-2532). The mechanistic foundations underpinning isomerization selectivity are discussed together with induction models and rationales to explain the counterintuitive directionality of these processes in which very small energy differences distinguish substrate from product. Implications for subsequent stereospecific transformations, application in total synthesis, regioselective polyene isomerization, and spatiotemporal control of pre-existing alkene configuration in a broader sense are discussed.

Assessing Arsenic Species in Foods Using Regularized Linear Regression of the Arsenic K-edge X-ray Absorption Near Edge Structure.

The toxicity and bioavailability of arsenic is heavily dependent on its speciation. Therefore, robust and accurate methods are needed to determine arsenic speciation profiles for materials related to public health initiatives, such as food safety. Here, X-ray spectroscopies are attractive candidates as they provide in situ, nondestructive analyses of solid samples without perturbation to the arsenic species therein. This work provides a speciation analysis for three certified reference materials for the food chemistry community, whose assigned values may be used to assess the merit of the X-ray spectroscopy results. Furthermore, extracts of SRM 3232 Kelp Powder, which is value-assigned for arsenic species, are measured to provide further evidence of its efficacy. These analyses are performed on the results of As K-edge X-ray Absorption Near Edge Structure (XANES) measurements collected on each sample. Notably, such analyses have traditionally relied on linear combination fitting of a minimal subset of empirical standards selected by stepwise regression. This is known to be problematic for compounds with meaningfully collinear spectra and can yield overestimates of the accuracy of the analysis. Therefore, the least absolute shrinkage and selection operator (lasso) regression method is used to reduce the risk of overfitting and increase the interpretability of statistical inferences. As this is a biased statistical method, results and uncertainties are estimated using a bootstrap method accounting for the dominant sources of variability. Finally, this method does not separate model and data selection from regression analysis. Indeed, a survey of many spectral influences is presented including changes in the: state of methylation, state of protonation, oxidation state, coordination geometry, and sample phase. These compounds were all included in the model's training set, preventing model over-simplification and enabling high-throughput and robust analyses.

Leveraging the n→π* Interaction in Alkene Isomerization by Selective Energy Transfer Catalysis.

Examples of geometric alkene isomerization in nature are often limited to the net exergonic direction (ΔG°<0), with the antipodal net endergonic processes (ΔG°>0) comparatively under-represented. Inspired by the expansiveness of the maleate to fumarate (Z→E) isomerization in biochemistry, we investigated the inverse E→Z variant to validate nO →πC=O * interactions as a driving force for contra-thermodynamic isomerization. A general protocol involving selective energy transfer catalysis with inexpensive thioxanthone as a sensitizer (λmax =402 nm) is disclosed. Whilst in the enzymatic process nO →πC=O * interactions commonly manifest themselves in the substrate, these same interactions are shown to underpin directionality in the antipodal reaction by shortening the product alkene chromophore. The process was validated with diverse fumarate derivatives (>30 examples, up to Z:E>99:1), including the first examples of tetrasubstituted alkenes, and the involvement of nO →πC=O * interactions was confirmed by X-ray crystallography.

Assessing the microscale heterogeneity in Standard Reference Material 4600 Surrogate Post-detonation Urban Debris.

Nondestructive microbeam X-ray fluorescence (µXRF) spectrometry has been used to investigate the elemental microheterogeneity in a nuclear forensics reference material (RM), NIST SRM 4600 Surrogate Post-detonation Urban Debris. Using a principal component analysis (PCA) model, results indicate the majority of elements appear homogeneous; however, zinc (Zn) exhibits microscale heterogeneity for this SRM. To minimize contributions to the measurement uncertainty from elemental microheterogeneity, a minimum sample mass of 24 mg is recommended for analysis.

A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis.

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the i Pr group is reported. The difluorination of readily accessible α-CF3 -styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2 F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X-ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.

Coumarins by Direct Annulation: ß-Borylacrylates as Ambiphilic C3 -Synthons.

Modular ß-borylacrylates have been validated as programmable, ambiphilic C3 -synthons in the cascade annulation of 2-halo-phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2 )-C(sp2 ) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre-condition to access 3-substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π-expanded estrone derivatives modified at the A-ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Boron-enabled geometric isomerization of alkenes via selective energy-transfer catalysis.

Isomerization-based strategies to enable the stereodivergent construction of complex polyenes from geometrically defined alkene linchpins remain conspicuously underdeveloped. Mitigating the thermodynamic constraints inherent to isomerization is further frustrated by the considerations of atom efficiency in idealized low-molecular weight precursors. In this work, we report a general ambiphilic C3 scaffold that can be isomerized and bidirectionally extended. Predicated on highly efficient triplet energy transfer, the selective isomerization of ß-borylacrylates is contingent on the participation of the boron p orbital in the substrate chromophore. Rotation of the C(sp2)-B bond by 90° in the product renders re-excitation inefficient and endows directionality. This subtle stereoelectronic gating mechanism enables the stereocontrolled syntheses of well-defined retinoic acid derivatives.

Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study.

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C-F stereocentre in high enantioselectivity, and is also amenable to stereogenic C-CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.

Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring.

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri.